Hodgkin lymphoma: clinical guidelines

Applies toadults, children2025 editionC81

Clinical guidelines of the Russian Ministry of Health, adults, children. 2025 edition, ICD-10 code: C81. This page features a shortened version by WhiteCoat Pro and the full official text.

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Brief for Practice

WhiteCoat Pro editorial summary of the guideline text, 2025 edition. Each item links to the original section — verify against it before prescribing.

Hodgkin lymphoma is a B-cell malignant lymphoproliferative disorder; classical and nodular lymphocyte-predominant Hodgkin lymphoma are distinguished. The guideline covers morphological verification, staging, PET-adapted treatment, management of relapses, and follow-up in children and adults.

Key points

The diagnosis is established exclusively via biopsy with morphological and immunohistochemical examination; a cytological examination of puncture aspirate alone is insufficient for nosological verification. → in text
After confirmation of the HL type and histological subtype, staging is mandatory; for classical HL, the prognostic group is also determined. → in text
B symptoms include fever above 38 °C for at least 3 days without signs of inflammation, drenching night sweats, and a 10% weight loss over 6 months. → in text
Each cycle of therapy is initiated when the patient's general condition is satisfactory, with granulocytes > 1 × 10⁹/L and platelets > 100 × 10⁹/L; in cases of cytopenia due to bone marrow involvement, treatment may be initiated at lower values with appropriate supportive care. → in text
Interim PET/CT in classical HL, if baseline staging was performed using PET/CT, is conducted after the 2nd cycle; metabolic response is assessed using the Deauville scale. → in text
In case of disease relapse or progression, a repeat biopsy is strongly recommended, preferably from the lesion with the maximum [18F]FDG uptake; repeat biopsy confirms the diagnosis, verifies tumor transformation, and rules out a second malignancy or infectious process. → in text
Following complete remission, adult patients are monitored by an oncologist or hematologist: every 3 months during the first year, every 6 months during the second year, then annually, and every 2 years after 5 years. → in text

Diagnostics

Take a medical history, including a family history of lymphoproliferative disorders; assess the rate of lymph node enlargement, B symptoms, and signs of mediastinal involvement. → in text
Perform a physical examination, evaluate ECOG performance status, examine the skin, tonsils, and oral cavity; palpate accessible lymph node groups, the liver, and the spleen. → in text
Perform a complete blood count with differential, absolute lymphocyte count, and ESR, along with a comprehensive metabolic panel and coagulogram. Prior to first-line therapy, also determine blood type and Rh factor, and perform molecular testing for HBV, HCV, HIV-1, EBV, CMV, and herpes simplex virus. → in text
Obtain adequate tissue material from a lymph node or other lesion for biopsy and perform morphological examination with immunohistochemistry; initial diagnosis requires an excisional or incisional/excisional biopsy, while fine-needle aspiration of lymph nodes for cell suspension is strictly discouraged. → in text
For staging, response assessment, and detection of relapse, perform contrast-enhanced CT of the neck, chest, abdomen, and pelvis; when available, supplement with [18F]FDG-PET/CT. → in text
Determine the stage using the Ann Arbor/Cotswold classification and assign the patient to an early favorable prognosis, early unfavorable prognosis, or advanced disease group; for advanced stages, use the IPS. → in text
Assess the indication for bone marrow trephine biopsy. For stage I–II disease strictly above the diaphragm, without focal bone or bone marrow involvement on PET/CT and without cytopenia or thrombocytosis, it may be omitted (level of reliable evidence [LoRE] B, grade of recommendation [GoR] 2); in the absence of PET/CT, with subdiaphragmatic involvement, or in stage III–IV disease, trephine biopsy is mandatory. → in text

Treatment

In patients aged 18–60 years with early-stage classical HL and a favorable prognosis, 2–4 cycles of ABVD are administered, followed by radiotherapy at 20–30 Gy in 10–15 fractions if a complete metabolic response (Deauville 1–3) is achieved (LoRE B, GoR 2). → in text
For early-stage classical HL with an unfavorable prognosis and accelerated ESR and/or involvement of 3 or more lymph node areas, 4 cycles of ABVD and radiotherapy at 30 Gy in 15 fractions are administered for Deauville 1–3 response (LoRE A, GoR 1). If staging was performed by CT only without PET/CT, and the patient does not meet the criteria for 4 cycles of ABVD, 6 cycles of ABVD and radiotherapy at 30 Gy in 15 fractions are used; the same option is provided in case of comorbidities precluding 2 cycles of escalated BEACOPP + 2 cycles of ABVD (LoRE A, GoR 1). → in text
In advanced classical HL without B symptoms, IPS 0–2, and without absolute lymphopenia < 0.6 × 10⁹/L, ABVD is prescribed; with complete remission after the 2nd or 4th cycle, a total of 6 cycles is typically administered (LoRE A, GoR 1). → in text
In advanced HL without B symptoms in patients aged 18–50 years with IPS 3–7, as well as in all patients with advanced HL with B symptoms, BEACOPP-14 (8 cycles) or escalated BEACOPP (6 cycles) is used; EACOPP-14 (6 cycles) is an alternative. In case of complete metabolic response and a residual mass of at least 2.5 cm, radiotherapy at 30 Gy is administered (for BEACOPP regimens — LoRE A, GoR 1; for EACOPP-14 — LoRE C, GoR 4). → in text
Escalated BEACOPP, BEACOPP-14, and EACOPP-14 require routine primary prophylaxis of neutropenia with G-CSF (LoRE B, GoR 2). For short-acting G-CSF, administration starts on day 9; for pegylated G-CSF, it starts on days 4–5 for BEACOPP-14/EACOPP-14 or on day 9 for escalated BEACOPP. → in text
In patients over 60 years of age, the regimen is chosen individually, accounting for comorbidities. In case of major contraindications to polychemotherapy, metronomic therapy or monotherapy is an option; examples include vinblastine 5.5 mg/m² IV every 14 days, etoposide 50 mg/m², or cyclophosphamide 50–150 mg orally in 7- to 14-day courses. → in text
In refractory HL, early relapse, or late relapse with high tumor burden, patients eligible for HDT undergo second-line therapy to achieve PET-negative remission, stem cell mobilization, followed by HDT with autologous HSCT. Following hematopoietic recovery after autologous HSCT, brentuximab vedotin for 16 infusions is recommended for high-risk relapse patients (for adults — LoRE A, GoR 2). → in text
In cases of massive tumor burden, tumor lysis syndrome prophylaxis is performed: allopurinol 10 mg/kg/day, hydration at 3 l/m²/day with sodium bicarbonate 40–80 mmol/L, urine output monitoring, and furosemide 1–10 mg/kg; for symptomatic hypogammaglobulinemia associated with a history of severe infection and an IgG level < 4 g/L, immunoglobulin 0.2–0.4 g/kg IV every 3–4 weeks for 12 months is prescribed. → in text

When to refer and how to monitor

Planned hospitalization is indicated to initiate or routinely continue specific therapy, as well as for diagnostic procedures requiring inpatient settings. → in text
Emergency hospitalization is indicated for complications of the underlying disease requiring specific inpatient treatment, as well as for life-threatening complications of specific therapy requiring appropriate inpatient management. → in text
In refractory disease, early relapse, or late relapse with high tumor burden, patients under 50 years of age with an ECOG performance status of 0–1 are referred to a transplant center to evaluate for HDT with autologous HSCT; in select cases, this is also possible at ages 50–60. → in text
In nodular lymphocyte-predominant Hodgkin lymphoma with recurrent relapses without signs of transformation, a transplant center consultation is also required to assess the feasibility of autologous HSCT. → in text
Transfer to the ICU is required in cases of sepsis or septic shock, acute respiratory or renal failure, stroke, life-threatening arrhythmias, or massive gastrointestinal bleeding. → in text

Frequently asked questions

How is Hodgkin lymphoma diagnosed?

Exclusively by tissue biopsy examination: morphological and immunohistochemical studies are performed. Cytology of a puncture aspirate or touch imprint is supplementary and does not replace tissue verification. → in text

What do PET/CT Deauville scores 1–3 or 4–5 mean?

Deauville 1–3 corresponds to a complete metabolic response. Deauville 4–5 indicates a PET-positive result; it is interpreted in conjunction with response dynamics: decreased uptake indicates a partial response, no change indicates stable disease, and increased uptake or new lesions indicate progression. → in text

When is interim PET/CT performed after chemotherapy?

It is performed after the 2nd cycle, within the 2 days immediately preceding the 3rd cycle. For 14-day regimens, the study is performed on days 12–15 from the start of the 2nd cycle, but no later than the 17th day; for 21-day regimens, on days 14–20, but no later than the 23rd day. → in text

Is it mandatory to perform a bone marrow trephine biopsy?

In cHL stages I–II only above the diaphragm, without focal bone or bone marrow involvement according to PET/CT, and without cytopenia or thrombocytosis, omitting the trephine biopsy is acceptable (LoR B, LoE 2). In stages III–IV, infradiaphragmatic involvement, or in the absence of PET/CT, it is mandatory. → in text

How to treat HL during pregnancy?

The management strategy is chosen by a multidisciplinary team consisting of a hematologist and an obstetrician-gynecologist; the diagnosis must be morphologically verified, and ultrasound and MRI are preferred for staging. In case of B-symptoms, superior vena cava syndrome, or the threat of progression, vinblastine 6 mg/m², but not more than 10 mg, is recommended every 10–14 days until delivery. → in text

Status: Applied · approved by the Scientific and Practical Council of the Russian Ministry of Health
Database ID: 139, edition 2 (ID 139_2)
Publication date: January 20, 2025
Age category: adults, children
ICD-10 codes: C81
Specialties: Oncology Hematology Transplantology
Developers: Russian Association of Oncologists
National Society of Pediatric Hematologists and Oncologists
Russian Professional Society of Oncohematologists
Non-Profit Partnership for the Promotion of Hematology and Bone Marrow Transplantation "National Hematological Society"
Official text: Russian Ministry of Health Guidelines Rubricator — 139_2

Abbreviated Clinical Guidelines: Hodgkin Lymphoma

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Beginning of abbreviated version — open

Terms and Definitions

ECOG — Eastern Cooperative Oncology Group performance status scale.

B-symptoms — nonspecific symptoms of tumor intoxication. Include:
Fever above 38°C (for at least 3 consecutive days without signs of inflammation).
Drenching night sweats.
Weight loss of 10% of body weight over the last 6 months.

1.1 Definition

Hodgkin Lymphoma (HL) is a B-cell malignant lymphoproliferative disorder.

1.2 Etiology and Pathogenesis

Etiology: unknown.

Cellular composition of the tumor population:
Hodgkin cells.
Reed-Sternberg cells.
Lacunar cells.
Mummified cells.
LP cells.
Pathogenetic feature: HL is characterized by a prominent reactive polymorphic cellular microenvironment.

1.3 Epidemiology

Incidence in the Russian Federation: 2.2 cases per 100,000 population per year.

Mortality: 0.61 cases per 100,000 population per year.
Age structure: occurs at any age, but predominantly between 16 and 35 years.
Gender structure: in the 16–35 age group in Russia, females predominate.

C81 — Hodgkin lymphoma.
C81.0 — Nodular lymphocyte-predominant Hodgkin lymphoma.

C81.1 Nodular sclerosis (classical) Hodgkin lymphoma.
C81.2 Mixed cellularity (classical) Hodgkin lymphoma.
C81.3 Lymphocyte depletion (classical) Hodgkin lymphoma.
C81.4 Lymphocyte-rich (Lymphocyte-rich) (classical) Hodgkin lymphoma.
C81.7 Other forms of (classical) Hodgkin lymphoma.
C81.9 Hodgkin lymphoma, unspecified.

1.5 Classification (WHO 2017)

According to the revised WHO classification (2017), two main types of Hodgkin lymphoma (HL) are distinguished:

Classical HL (cHL) — ICD-10 codes C81.1–C81.9.
Nodular lymphocyte-predominant HL (NLPHL) — ICD-10 code C81.0 (Nodular lymphocyte-predominant type).

Histological variants of classical HL:

Nodular sclerosis variant (types I and II).
Mixed cellularity variant.
Lymphocyte-rich classical variant (lymphocyte-rich).
Lymphocyte depletion variant (rare).

Mandatory components of the diagnosis:

Every patient must have the following determined:

HL type and histological variant (for cHL).
Disease stage.
Risk group (for cHL).

1.6 Clinical Presentation

Main symptoms:

Lymphadenopathy: asymptomatic enlargement of peripheral lymph nodes.
Intoxication symptoms (B-symptoms):
Fever above 38°C (for at least 3 consecutive days without signs of inflammation).
Drenching night sweats.
Weight loss of 10% over the last 6 months.

Intermittent fever.
Pruritus (prior to scratching/excoriations).

Symptoms of bulky mediastinal disease:

Chest pain.
Cough, dyspnea.
Superior vena cava compression symptoms (SVC syndrome).

Phenomenon of lymph node pain after alcohol consumption:
An extremely rare, but characteristic and consistent symptom.
Localization: in the affected lymph nodes.

Features of the evidence base:

Many methods have a low level of recommendation (LoR) and level of evidence (LoE) due to the lack of specific clinical trials.
Despite this, these methods are mandatory for establishing the diagnosis and choosing the treatment strategy, as there are no more effective alternatives at present.

Diagnostic criteria:

The diagnosis of Hodgkin lymphoma (HL) is established solely on the basis of:
Morphological examination of biopsy material.
Immunohistochemical (IHC) examination of biopsy material.
The formulation of the diagnosis must comply with the WHO 2017 revised classification of tumours of haematopoietic and lymphoid tissues.

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List of Abbreviations

GTV — gross tumor volume

CTV — clinical target volume

PTV — planning target volume

ALT — alanine aminotransferase

AST — aspartate aminotransferase

auto-HSCT — autologous hematopoietic stem cell transplantation

aPTT — activated partial thromboplastin time

HDCT — high-dose chemotherapy

GCS — glucocorticoids (H02AB group according to the ATC classification)

G-CSF — colony-stimulating factors (L03AA)

DLBCL — diffuse large B-cell lymphoma

cHL — classical Hodgkin lymphoma

CT — computed tomography

LDH — lactate dehydrogenase

RT — radiotherapy

HL — Hodgkin lymphoma

INR — international normalized ratio

IPI — International Prognostic Index

NLPHL — nodular lymphocyte-predominant Hodgkin lymphoma

RP — radiopharmaceuticals for the diagnostics of neoplasms

CR — complete remission

PET/CT — positron emission tomography combined with computed tomography

TAD — total absorbed dose

ESR — erythrocyte sedimentation rate

CT — chemotherapy

** — vital and essential drugs

# — off-label drug use (not in accordance with the indications, contraindications, routes of administration, and dosages contained in the product leaflet)

ECG – electrocardiography

EchoCG – echocardiography

Terms and Definitions

ECOG — Eastern Cooperative Oncology Group performance status scale — see Appendix G1.

B-symptoms — nonspecific symptoms of tumor intoxication, including fever above 38°C for at least three consecutive days without signs of inflammation; profuse night sweats; weight loss of 10% of body weight over the last 6 months.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hodgkin lymphoma (HL) is a B-cell malignant lymphoproliferative disorder [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of HL is unknown. The tumor population of HL includes Hodgkin cells, Reed-Sternberg cells, lacunar, mummified, and LP cells. HL is characterized by a prominent reactive polymorphous cellular microenvironment [1].

1.3 Epidemiology of the Disease or Condition

The incidence of Hodgkin lymphoma (HL) in Russia is 2.2 cases per 100,000 population per year, and mortality reaches 0.61 cases per 100,000 population per year (in 2016, 3,129 new cases were diagnosed, and 879 patients died). The disease occurs at any age, but predominantly between 16 and 35 years; in this age group in Russia, females predominate among affected individuals [2].

1.4 Features of Coding the Disease or Condition

C81 — Hodgkin lymphoma

C81.0 Nodular lymphocyte-predominant Hodgkin lymphoma
C81.1 Nodular sclerosis (classical) Hodgkin lymphoma
C81.3 Lymphocyte-depleted (classical) Hodgkin lymphoma
C81.4 Lymphocyte-rich classical Hodgkin lymphoma
C81.7 Other forms of (classical) Hodgkin lymphoma
C81.9 Hodgkin lymphoma, unspecified

1.5 Classification of the disease or condition

The WHO 2017 revised classification of tumours of haematopoietic and lymphoid tissues distinguishes two types of HL: classical HL (cHL) (ICD-10 C81.1–C81.9) and nodular lymphocyte-predominant HL (NLPHL) (ICD-10: C81.0 Nodular lymphocyte-predominant Hodgkin lymphoma). Classical HL includes the following histological variants: nodular sclerosis (type I and II), mixed cellularity, lymphocyte-rich classical, and the rare lymphocyte-depleted variant (morphological and immunohistochemical diagnosis of various HL variants is detailed in Section 7.1 of these guidelines) [3].

In addition to determining the type of HL and the histological variant of cHL, the disease stage must be determined for every patient, and for cHL, the risk group as well (see Section 7.3 of these guidelines) [4].

1.6 Clinical presentation of the disease or condition

Clinical symptoms of the disease may include [4]:

asymptomatic enlargement of peripheral lymph nodes;
symptoms of intoxication (B-symptoms: fever above 38°C for at least three consecutive days without signs of inflammation; drenching night sweats; weight loss of 10% of body weight over the last 6 months);
intermittent fever;
pruritus leading to excoriations;
in patients with massive mediastinal involvement — chest pain, cough, dyspnea, superior vena cava syndrome;
an extremely rare, but characteristic and persistent symptom — pain in the affected lymph nodes after alcohol consumption.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended diagnostic methods for the disease and related conditions have a limited evidence base (according to the trustworthiness of evidence and recommendation grading scales) due to the lack of dedicated clinical studies. Despite this, they are necessary components of patient evaluation to establish a diagnosis and select treatment tactics, as more effective and evidence-based methods have not yet been developed.

Criteria for establishing the diagnosis/condition: the diagnosis of Hodgkin lymphoma is established solely on the basis of morphological and immunohistochemical analysis of biopsy material and is formulated in accordance with the 2017 WHO classification of tumours of hematopoietic and lymphoid tissues. [1, 3].

2.1 Complaints and Anamnesis

In all patients with suspected or confirmed HL at the initial visit, taking a history of blood and hematopoietic organ diseases is recommended [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: when taking the history, it is necessary to clarify, among other things, the family history, paying attention to the presence of lymphoproliferative disorders.

In all patients with suspected or confirmed HL at the initial or follow-up visit, before each subsequent cycle of chemotherapy, during response assessment 2 months after therapy completion, during follow-up examinations, and when disease relapse is suspected, taking a history regarding blood and hematopoietic organ diseases is recommended [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: during the initial examination, special emphasis should be placed on the timing and rate of lymph node enlargement (the main symptom of HL is lymphadenopathy developing gradually and asynchronously), non-specific intoxication symptoms (fever above 38°C for at least three consecutive days without signs of inflammation; drenching night sweats; weight loss of 10% of body weight over the last 6 months), and upper mediastinal involvement symptoms (persistent non-productive cough, superior vena cava syndrome, hoarseness, dysphagia, dyspnea).

2.2 Physical Examination

In all patients with suspected or confirmed HL at the initial or follow-up visit, before each subsequent cycle of chemotherapy, during response assessment 2 months after therapy completion, during follow-up examinations, and when disease relapse is suspected, performing a physical examination (inspection, palpation, and auscultation) is recommended to determine the extent and severity of the disease [1].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: during the examination, it is necessary to evaluate the patient's general condition using the ECOG scale (see Appendix G1), as well as inspect the skin, tonsils, and oral cavity; palpation must include all accessible peripheral lymph node groups, the liver, and the spleen.

2.3 Laboratory Diagnostics

In all patients with suspected or confirmed HL at the initial or follow-up visit, before the start of each new therapy cycle, during response assessment after therapy completion, during follow-up examinations, and when disease relapse is suspected, performing the following diagnostic tests is recommended to assess the patient's condition, plan therapeutic tactics, determine the need for their modification, and assess the need for supportive and concomitant therapy [1]:

complete blood count (CBC) with differential, including hemoglobin, erythrocytes, platelets, leukocytes, reticulocytes, leukocyte differential count with absolute leukocyte count, and erythrocyte sedimentation rate (ESR);
urinalysis (may be omitted at follow-up visits, before the start of each new therapy cycle, during response assessment after therapy completion, during follow-up examinations, and when disease relapse is suspected, if the patient has no specific complaints or symptoms, the previous urinalysis was within normal limits, and there were no prior episodes of febrile neutropenia);
general clinical blood chemistry panel including the following parameters: blood lactate dehydrogenase (LDH) activity, blood urea level, blood creatinine level, blood glucose level, total blood protein level, blood albumin level, total blood bilirubin level, blood aspartate aminotransferase (AST) activity, blood alanine aminotransferase (ALT) activity, blood alkaline phosphatase (ALP) activity, blood potassium level, blood sodium level, blood chloride level, total blood calcium level (other routine chemistry parameters may be included at the physician's discretion);
coagulogram (screening hemostasis panel) including the following parameters: prothrombin time (PT) in blood or plasma, international normalized ratio (INR), activated partial thromboplastin time (APTT), blood fibrinogen level, thrombin time, blood antithrombin III activity, blood plasminogen level, and blood D-dimer concentration (may be omitted at follow-up visits, before the start of each new therapy cycle, during response assessment after therapy completion, during follow-up examinations, and when disease relapse is suspected, if the patient has no specific complaints or symptoms and previous tests were within normal limits).

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: assessing the absolute lymphocyte count in peripheral blood before treatment is necessary for the optimal selection of first-line chemotherapy — it is included as a risk factor in the International Prognostic Score for advanced-stage classical Hodgkin lymphoma (see section 7.3 of these guidelines).

In all previously untreated HL patients before initiating first-line antineoplastic therapy, determining ABO blood groups and Rh factor (D antigen) is recommended to allow for blood transfusion if indicated before, during, or after therapy [1].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

In all previously untreated HL patients before initiating first-line antineoplastic therapy, performing the following tests is recommended to rule out concomitant infectious diseases and plan necessary supportive therapy [1]:

molecular biological blood testing for Hepatitis B virus and Hepatitis C virus;
molecular biological blood testing for human immunodeficiency virus HIV-1;
molecular biological blood testing for Epstein-Barr virus, cytomegalovirus, and herpes simplex virus.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

In all HL patients under 18 years of age prior to starting antineoplastic therapy, as well as in all HL patients regardless of age receiving or having received antineoplastic therapy after the first episode of a severe infection, assessing immune status (serum immunoglobulin G, A, and M levels) is recommended to clarify the risk of infectious complications and the need for appropriate prophylaxis [5, 6].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: if IgG <4 g/L, the clinical situation is regarded as symptomatic hypogammaglobulinemia. In such cases, immunoglobulin replacement therapy is indicated (see section "Supportive and Concomitant Therapy").

In women of childbearing potential with newly diagnosed or relapsed HL, before starting therapy, undergoing a comprehensive pregnancy evaluation is recommended to adjust therapeutic tactics, along with an initial consultation with an obstetriciangynecologist if pregnancy is present and the patient wishes to carry it to term [1, 7].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

In women of childbearing potential with newly diagnosed HL for whom intensive chemotherapy regimens (BEACOPP escalated, BEACOPP-14, EACOPP-14) are planned, an initial consultation with an obstetrician-gynecologist before starting treatment is recommended to discuss ovarian protection strategies [9, 159].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

In women of childbearing potential with newly diagnosed advanced-stage HL without B-symptoms and with an ECOG performance status of 0–1, for whom intensive chemotherapy (6 cycles of escalated BEACOPP or 8 cycles of BEACOPP-14, 6 cycles of EACOPP-14) is planned, as well as those with relapsed HL scheduled for high-dose chemotherapy (HDCT), an initial consultation with an obstetrician-gynecologist is recommended to address ovarian tissue cryopreservation [8, 9].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

In young men with newly diagnosed HL for whom intensive BEACOPP chemotherapy and its modifications are planned, discussing sperm cryopreservation for fertility preservation is recommended [9–11].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

2.4 Instrumental Diagnostics

In all patients at the time of HL diagnosis, during treatment response evaluation, and when disease relapse is suspected, performing computed tomography (CT) of the neck, chest, abdomen, and pelvis (with intravenous bolus contrast enhancement) is recommended for staging and assessing the presence, size, and extent of tumor lesions [1, 152].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For patients with contraindications to CT or when CT is not feasible, upon establishing the diagnosis of HL, when assessing treatment response, and when disease relapse is suspected, it is recommended to perform the following diagnostic examinations for disease staging and to clarify the presence, size, and extent of tumor lesions [1]:

Targeted chest X-ray in two projections;
ultrasound examination of the lymph nodes (ultrasound examination of lymph nodes (one anatomical zone)) and abdominal organs (comprehensive).

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: ultrasound examination should evaluate peripheral lymph nodes, intra-abdominal and retroperitoneal nodes, abdominal and pelvic organs (ultrasound examination of lymph nodes (one anatomical zone), comprehensive ultrasound of abdominal organs, comprehensive ultrasound of pelvic organs). Lymph nodes less than 1 cm in diameter are considered unaffected, lymph nodes 1–2 cm in diameter require dynamic monitoring during therapy, and lymph nodes greater than 2 cm in diameter are considered affected.

For all patients upon establishing the diagnosis of HL, when assessing treatment response, and when disease relapse is suspected, it is recommended—if available—to perform positron emission tomography combined with computed tomography using the tumor-tropic radiopharmaceutical [18F]fluorodeoxyglucose for more accurate disease staging and better assessment of the therapeutic effect [1, 4, 12].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: positron emission tomography combined with computed tomography (PET/CT) (positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals with contrast enhancement) is a highly informative diagnostic method. PET/CT performed before treatment initiation allows not only staging clarification but also a more precise determination of lesion localization, which is essential for the subsequent assessment of induction therapy efficacy, quality planning of subsequent radiation therapy, and minimization of radiation exposure to healthy tissues. If PET/CT is available, it can be used in accordance with revised response criteria, primarily in patients with minimal tumor burden, and considering potential treatment adjustments.

PET/CT is required in patients with early-stage HL, as this enables PET-adapted therapy in these patients.

Over the past decade, the advantage of PET-adapted therapy in the treatment of cHL has been proven [13–16]. Treatment regimen correction is based on the results of interim PET/CT performed after the second cycle of chemotherapy. Therefore, all patients with cHL who underwent staging via PET/CT are strongly recommended to undergo a PET/CT scan after the 2nd cycle of chemotherapy, provided the inter-cycle interval is maintained. The PET/CT scan should be performed within the 2 days immediately preceding the 3rd cycle of chemotherapy, specifically on days 12–15 (but no later than the 17th day) from the start of the 2nd cycle for 14-day antitumor drug administration regimens (ABVD, BV-AVD, BEACOPP-14, EACOPP-14 and its modifications with dacarbazine**), and on days 14–20 (but no later than the 23rd day) for 21-day cycles (escalated BEACOPP, etc.), since an increase in the planned interval between cycles of 3 days or more leads to a failure in delivering the full-dose treatment regimen, which reduces therapy efficacy and increases the risk of relapse. If interim PET/CT cannot be performed within the specified time intervals, the PET-2-adapted treatment program should be abandoned, and the PET/CT scan postponed to the post-chemotherapy evaluation stage.

Regardless of the PET/CT results after the 2nd cycle, a PET/CT scan is also performed at the end of the chemotherapy phase, as the decision on prescribing radiation therapy or another type of treatment is based on the results of this scan. The PET/CT scan after the end of the chemotherapy phase should be performed 14–21 days after the last administration of antitumor drugs, since if radiation consolidation is required, RT must be started no later than the 6th week after the end of chemotherapy.

At any stage of treatment outcome evaluation, the magnitude of the treatment effect should be assessed using the Deauville scale (see Appendix G2).

For children, the use of PET/CT is highly desirable, as the level of metabolic response after induction therapy determines the need for radiation therapy for each patient.

If PET/CT is feasible, bone marrow involvement in children and adolescents is diagnosed in the presence of more than two PET-positive skeletal lesions, regardless of CT or MRI data. The diagnosis of bone involvement in cHL is made based on a combination of characteristic PET and CT findings, or the results of bone scintigraphy.

If PET/CT is not available, staging is performed based on CT of the neck, chest, abdomen, and pelvis with intravenous and X-ray contrast enhancement.

For all patients with a confirmed diagnosis of HL for whom treatment is planned for newly diagnosed disease or relapse, electrocardiography is recommended to evaluate cardiac function [1, 4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For all patients with a confirmed diagnosis of HL scheduled for treatment with the antitumor antibiotic (L01DB anthracyclines and related substances) doxorubicin** (in ABVD, BEACOPP, OEPA regimens—see Appendix A3.1), as well as for patients with impaired cardiac function receiving this treatment, echocardiography with determination of the ejection fraction is recommended to monitor cardiac toxicity [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For patients with a confirmed diagnosis of HL scheduled for treatment with the antitumor antibiotic (L01DC other antitumor antibiotics) bleomycin** (in ABVD and BEACOPP regimens—see Appendix A3.1) who have a history of pneumonitis of any origin, chronic lung diseases (COPD, severe bronchial asthma, etc.), or data on radiation therapy to the chest area, a study of unforced respiratory volumes and flows (spirometry) is recommended to decide on the administration of bleomycin**; also for patients with impaired lung function receiving this treatment to monitor pulmonary toxicity [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For all patients with a verified diagnosis of HL, given the necessity of prescribing glucocorticoids, the following examinations are recommended before therapy initiation for the timely detection of comorbid conditions and to determine the need for their prevention or treatment [4, 17]:

esophagogastroduodenoscopy;
ultrasound duplex scanning of lower extremity vessels (arteries and veins).

RG CLE 5Recommendation Grade C (Level of Evidence 5).

2.5 Other Procedures

For all patients with suspected HL, as well as all patients with suspected HL relapse (if technically feasible), a biopsy (obtaining biopsy material) of a lymph node or other lesion site, and pathomorphological examination of the biopsy (surgical) material using immunohistochemical methods are recommended to verify the diagnosis [1, 4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: the choice of tissue and the volume of the biopsy must be adequate for the diagnostic task at hand.

Fine-needle biopsies of lymphoid tissue can be diagnostically significant, but not always.
Marginal biopsies of lymphoid tissue have low diagnostic value.
Tissue fragmentation severely impedes its evaluation.
It is advisable to coordinate the scope of the biopsy with the pathologist.
The presence of a pathologist during the biopsy is highly desirable.
Material for pathomorphological examination must be placed in a fixative medium as quickly as possible. Drying of the material must not be allowed.
The ratio of the volume of the fixative medium to the volume of the fixed object must be at least 10:1.
Fixation time must not be less than 12 and more than 48 hours.

Inadequate (weak or excessive) fixation alters the morphological properties of the tissue and leads to artifactual IHC results.

Histological material must be accompanied by a referral form containing information about the patient, duration and nature of the disease, localization of the lesion site, and a description of the biopsy [18].

Diagnostic cavity surgeries—thoracoscopy/thoracotomy, laparoscopy/laparotomy with biopsy of intrathoracic, intra-abdominal lymph nodes, or liver—are performed only in the absence of enlarged peripheral lymph nodes and when diagnosis verification is impossible.

Histological and immunohistochemical characteristics of various HL variants, as well as mandatory requirements for the pathomorphological report, are presented in Section 7.1 of these guidelines. A description of the morphological and immunohistochemical picture of HL is presented in Section 7.2 of these guidelines.

For patients aged 18–60 years with verified early-stage cHL with a favorable prognosis and a PET-positive result after 4 cycles of ABVD (Deauville score 4–5, corresponding to "stable disease" or "progressive disease", Appendix G2), as well as with verified early-stage cHL with an unfavorable prognosis and a PET-positive result after 2 cycles of planned ABVD therapy (Deauville score 4–5, corresponding to "stable disease" or "progressive disease", Appendix G2), a biopsy of the PET-positive lymph node is recommended to select further treatment tactics [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For patients with cHL with no signs of bone marrow involvement according to PET/CT and no abnormalities in the complete blood count, except for patients with stage I–II cHL with involvement exclusively above the diaphragm, obtaining a bone marrow histological specimen (trephine biopsy) and a pathomorphological examination of the bone marrow biopsy (surgical) material using immunohistochemical methods are recommended to clarify the stage of the tumor process [19].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For patients with stage I–II cHL with involvement exclusively above the diaphragm and no focal bone/bone marrow lesions according to PET/CT results (except for patients with changes in the complete blood count — cytopenia or thrombocytosis), omitting the trephine biopsy is acceptable [20, 163, 164].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2).

Comments: in patients with stage I–II cHL with involvement exclusively above the diaphragm and no focal bone marrow lesions according to PET/CT results (except for patients with changes in the complete blood count — cytopenia and/or thrombocytosis), omitting the trephine biopsy is acceptable, since the probability of detecting bone marrow involvement in this group of patients when performing an iliac crest trephine biopsy is 0.4% [20].

For patients with stages I–II with involvement of lymphoid organs below the diaphragm, as well as for patients with stages III–IV who have not undergone PET/CT, performing a trephine biopsy is mandatory.

In most cases, if PET/CT demonstrates a homogeneous pattern of bone marrow radiopharmaceutical uptake (considered to be the result of cytokine release), bone marrow involvement is not suspected. The presence of focal bone/bone marrow lesions according to PET/CT (three or more lesions) suggests bone marrow involvement.

Performing PET/CT in children makes it possible to determine bone marrow involvement; therefore, performing a trephine biopsy is indicated only in doubtful cases.

If PET/CT is not available and staging is based solely on CT results, performing a bilateral iliac crest trephine biopsy is necessary for all stages. It is permissible not to perform an iliac crest trephine biopsy in stages I–IIA with lymph node involvement exclusively above the diaphragm without risk factors, signs of cytokine release in general clinical and biochemical blood tests, and cytopenia or thrombocytosis.

In children, iliac crest trephine biopsy must be performed under general anesthesia.

For all patients with NLPHL, regardless of the stage of the disease, a pathomorphological examination of the bone marrow biopsy (surgical) material (trephine biopsy) and a cytological examination of bone marrow trephine biopsy imprints are recommended.

For patients with cHL with focal bone/bone marrow lesions detected on PET/CT, obtaining a histological bone marrow specimen (trephine biopsy) is not recommended, except for doubtful cases [20, 163, 164].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2).

Comments: the results of large randomized trials by the German Hodgkin Study Group — HD16, HD17, HD18 — have demonstrated significant advantages of PET/CT over bone marrow trephine biopsy in diagnosing bone marrow involvement. The sensitivity and specificity of PET/CT were 99.2% and 100%, respectively [20].

For patients with HL prior to the first and subsequent lines of antineoplastic therapy, depending on the concomitant pathology, an initial consultation (examination) by a cardiologist, endocrinologist, neurologist, infectious disease specialist, and other medical specialists is recommended to determine the need for treatment of comorbid conditions [21].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

When choosing tactics and administering therapy, it should be taken into account that the patient may present with atypical disease manifestations or a combination of a specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for selecting optimal diagnostic and treatment tactics.

Each treatment cycle is initiated if the patient's condition meets the following criteria:

satisfactory general condition of the patient,
granulocytes >1 ´ 10⁹/L,
platelets >100 ´ 10⁹/L.

For patients with cytopenia caused by bone marrow involvement, specific therapy is feasible even at lower leukocyte and platelet counts, provided that appropriate supportive care is administered in such cases.

Recommendations for dose reduction and increasing intervals between therapy cycles are presented in Appendix A3.2.

The patient discontinues treatment according to the protocol in cases of disease progression or the onset of toxic effects that preclude continuing chemotherapy in the required volume.

RT in all HL treatment programs must be initiated 2 to 4 weeks after the end of chemotherapy, but no later than week 6.

3.1 First-line therapy for early-stage cHL in patients aged 18–60 years

For previously untreated patients aged 18–60 years with verified early-stage cHL with a favorable prognosis confirmed by PET/CT data, 2–4 cycles of combination chemotherapy according to the ABVD regimen (doxorubicin**, bleomycin**, vinblastine**, dacarbazine**) (for a description of regimens, see Appendix A3.1) followed by radiotherapy (RT) at a total dose of 20–30 Gy to the initial involvement sites in 10–15 fractions in case of a complete metabolic response to medical therapy according to PET/CT (Deauville score 1–3) are recommended [22–24].

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

Comment: in some patients, it is possible to limit treatment to 2–4 cycles of ABVD followed by RT at a TDF of 20 Gy to the initial involvement sites, provided that after a thorough modern examination using PET/CT they strictly meet the following criteria: initially no more than 2 involved areas, absence of extranodal involvement, bulky masses (no more than 5 cm on CT) and elevated ESR, and negative interim PET/CT results (PET-2 Deauville score 1–3 — see Appendix G2) after 2 cycles of CT.

For the remaining patients in this group, preference should be given to 4 cycles of ABVD, and in case of a complete response to medical therapy according to PET/CT (Deauville score 1–3) or CT, RT to the initially involved lymph nodes at 30 Gy is recommended [24].

For patients aged 18–60 years with verified early-stage cHL with a favorable prognosis in whom tumor cells are detected in the biopsy specimen of a PET-positive residual tumor lymph node after 4 cycles of ABVD, treatment intensification — administering two additional cycles of chemotherapy according to the escalated BEACOPP regimen (etoposide**, doxorubicin**, cyclophosphamide**, vincristine**, bleomycin**, procarbazine** or dacarbazine**, prednisolone**) (for a description of regimens, see Appendix A3.1) followed by RT at a dose of 30 Gy in 15 fractions to the initial involvement sites — is recommended [4, 25].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For previously untreated patients aged 18–60 years with verified early-stage cHL confirmed by PET/CT and with unfavorable prognostic factors such as an elevated ESR and/or involvement of 3 or more lymphatic collector regions, 4 cycles of combination chemotherapy according to the ABVD regimen (for a description of regimens, see Appendix A3.1) followed by RT to the initial involvement sites at a total dose of 30 Gy in 15 fractions in case of a complete response to medical therapy according to PET/CT (Deauville score 1–3) are recommended [26].

LeR ALoE 1Level of Evidence A (Level of Confidence of Evidence 1).

For previously untreated patients aged 18–50 years with verified stage I–IIA or IB cHL with bulky mediastinal lymph nodes and/or E-stage confirmed by CT or PET/CT and without severe comorbidities, 2 cycles of escalated BEACOPP + 2 cycles of ABVD (for a description of regimens, see Appendix A3.1) followed by RT at a dose of 30 Gy to the initial involvement sites are recommended [27].

Level of Recommendation ALevel of Evidence 2Level of recommendation A (level of evidence 2).

For previously untreated patients aged 18–60 years with early-stage cHL verified solely by CT data who did not undergo PET/CT, with unfavorable prognostic factors such as an elevated ESR and/or involvement of 3 or more lymphatic collector regions and therefore not meeting the criteria for 4 cycles of ABVD, as well as patients with comorbidity who cannot receive 2 cycles of escalated BEACOPP + 2 cycles of ABVD, 6 cycles of ABVD (for a description of regimens, see Appendix A3.1) followed by RT at a dose of 30 Gy in 15 fractions to the initial involvement sites are recommended [26].

LeR ALoE 1Level of Evidence A (Level of Confidence of Evidence 1).

For patients aged 18–60 years with verified early-stage cHL with an unfavorable prognosis in whom tumor cells are detected in the biopsy specimen of a PET-positive residual tumor lymph node after 2 cycles of planned therapy, treatment intensification — administering an additional 2–4 cycles of chemotherapy according to the escalated BEACOPP regimen (for a description of regimens, see Appendix A3.1) with CT or PET/CT monitoring after every 2 cycles and subsequent RT at a dose of 30 Gy in 15 fractions to the initial involvement sites in case of a complete response to medical therapy according to PET/CT (Deauville score 1–3) — is recommended [4, 25].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For treatment-naive patients over 18 years of age with verified stage I–IIA or IB cHL with bulky mediastinal lymph node conglomerates and/or E-stage, if baseline and interim PET/CT cannot be performed, it is recommended to administer therapy in accordance with the guidelines for advanced stages [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For patients with verified cHL who are indicated for radiation therapy, it is recommended, if technically feasible, to perform irradiation using proton therapy to reduce toxicity and the risk of secondary radioinduced tumors [28–30].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

3.2 First-line therapy for cHL, advanced stages, in patients aged 18–60 years

The standard treatment for advanced stages is chemotherapy combined with radiation therapy to the sites of large tumor masses remaining after chemotherapy.

In Russia, this group of patients is the most numerous, accounting for almost half of cHL cases. In addition, Russia still faces a severe shortage of transplantation beds, which precludes adequate therapy for disease relapses. Therefore, the primary objective in treating this group of patients is to achieve the maximum number of complete and sustained remissions as early as the first line of therapy.

For treatment-naive patients aged 18 to 60 years with advanced stages of cHL without B symptoms, with an IPS of 0–2, in the absence of absolute lymphocytopenia <0.6×10⁹/L, it is recommended to administer polychemotherapy according to the ABVD regimen (for a description of regimens, see Appendix A3.1) [26].

LeR ALoE 1Level of Evidence A (Level of Confidence of Evidence 1).

Comment: the number of ABVD cycles depends on the treatment response (evaluated after 2–4 cycles). A total of 6 cycles is recommended upon achieving complete remission after 2 and/or 4 cycles. The administration of 8 cycles upon achieving partial remission after 4 cycles is discouraged due to the increased cumulative dose of doxorubicin**. In the latter case, an alternative continuation of treatment may be discussed: upon achieving partial remission after 4 cycles of ABVD, administering only 2 additional cycles of ABVD (6 cycles in total) followed by radiation therapy to residual lymph nodes at a TDF of 30 Gy if a complete metabolic response is achieved on drug therapy according to PET/CT (Deauville score 1–3). Additional irradiation at a dose of 6 Gy ("boost") to individual residual lesions is possible (total dose 36 Gy).

For treatment-naive patients aged 18 to 50 years with advanced stages of cHL without B symptoms, but with an IPS of 3–7, and for all patients with advanced stages of cHL with B symptoms, it is recommended to administer polychemotherapy according to the BEACOPP-14 regimen (8 cycles) or escalated BEACOPP (6 cycles) (for a description of regimens, see Appendix A3.1) followed by irradiation of residual tumor masses measuring 2.5 cm or more at a TDF of 30 Gy if a complete metabolic response is achieved on drug therapy according to PET/CT (Deauville score 1–3) [26, 31].

LeR ALoE 1Level of Evidence A (Level of Confidence of Evidence 1).

Comment: if PET/CT was performed after completion of therapy to assess treatment efficacy, with a Deauville score metabolic response of 4–5, it is recommended to discuss second-line therapy. The decision to administer second-line therapy should be made based on a biopsy of the PET-positive lymph node, as the rate of false-positive PET/CT results at this stage is increased. In selected cases, irradiation of the metabolically active residual tumor site with a total dose of 36–40 Gy is possible.

For treatment-naive patients aged 18 to 50 years with advanced stages of cHL without B symptoms, but with an IPS of 3–7, and for all patients with advanced stages of cHL with B symptoms, as an alternative to the BEACOPP-14 or BEACOPPesc regimens, it is recommended to administer polychemotherapy according to the EACOPP-14 regimen (6 cycles) followed by irradiation of residual tumor masses measuring 2.5 cm or more at a TDF of 30 Gy if a complete metabolic response is achieved on drug therapy according to PET/CT (Deauville score 1–3) (for treatment response, see Appendix A3) [8].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

The escalated BEACOPP, BEACOPP-14, and EACOPP-14 regimens are characterized by higher myelotoxicity than the ABVD regimen and require mandatory scheduled administration of colony-stimulating factors (G-CSFs).

To reduce the manifestations of tumor lysis syndrome in patients with pronounced B symptoms and an ECOG performance status of 2 or higher, treatment may be initiated with a prephase: a single administration of vinblastine** (L01CA Vinca alkaloids and analogues) or cyclophosphamide** (L01AA nitrogen mustard analogues) as monotherapy or in combination with glucocorticoids for 1–3 days (in the absence of contraindications), or a single administration according to the ABVD regimen. Following the prephase, scheduled therapy with BEACOPP-14, escalated BEACOPP, and EACOPP-14 regimens should only be initiated after passing the leukocyte nadir.

For treatment-naive patients aged 50 to 60 years without severe comorbidities with advanced stages of cHL without B symptoms, but with an IPS of 3–7, and for all patients with advanced stages of cHL with B symptoms, it is recommended to administer polychemotherapy according to the BEACOPP-14 regimen (8 cycles) or EACOPP-14 regimen (6 cycles) (for a description of regimens, see Appendix A3.1) followed by irradiation of residual tumor masses measuring 2.5 cm or more at a TDF of 30 Gy if a complete metabolic response is achieved on drug therapy according to PET/CT (Deauville score 1–3) [8, 32].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: if PET/CT was performed after completion of therapy to assess treatment efficacy, with a Deauville score metabolic response of 4–5, it is recommended to discuss second-line therapy. The decision to administer second-line therapy should be made based on a biopsy of the PET-positive lymph node, as the rate of false-positive PET/CT results at this stage is increased. In selected cases, irradiation of the metabolically active residual tumor site with a total dose of up to 36-40 Gy is possible.

For all patients with advanced stages of cHL aged 18 to 60 years who received full-dose intensive drug therapy with escalated BEACOPP, BEACOPP-14, or EACOPP-14 regimens with a residual tumor ≤2.5 cm with a complete metabolic response (Deauville score 1–3) according to PET-2 and PET/CT after the completion of the chemotherapy phase of treatment, it is recommended to consider the possibility of omitting radiation therapy [31, 33].

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

For patients aged 18 to 60 years with advanced stages of cHL who underwent baseline PET/CT and presented with PET-positive lesions (Deauville score 4–5) after 2 cycles of ABVD, it is recommended to intensify therapy to escalated BEACOPP (4–6 cycles) or BEACOPP-14 (6 cycles) (for a description of regimens, see Appendix A3.1) [34].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

For patients aged 18 to 60 years with cHL receiving therapy with escalated BEACOPP, BEACOPP-14, or EACOPP-14 regimens, who underwent baseline PET/CT and presented with PET-positive lesions (Deauville score 4–5) after 2 cycles of chemotherapy, it is recommended to continue treatment according to the selected treatment program with PET monitoring after every 2 cycles [8, 34, 74].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

For all patients with cHL receiving therapy with escalated BEACOPP, BEACOPP-14, or EACOPP-14 regimens, it is recommended to prescribe scheduled G-CSFs (primary neutropenia prophylaxis) to ensure the administration of the next scheduled therapy cycle on time and with required blood counts [8, 35, 36].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2).

Comment: administration of short-acting G-CSFs begins on day 9 (1 day after vincristine** administration) regardless of the leukocyte count and continues until neutrophil recovery >1×10⁹/L and platelet recovery >100×10⁹/L, but only if the nadir has already been passed.

Administration of long-acting G-CSFs is performed on day 4 or 5 (when treated according to BEACOPP-14 or EACOPP-14 protocols) or on day 9 (when treated according to the escalated BEACOPP protocol) regardless of the leukocyte count and at least 24 hours after the completion of antineoplastic drug administration in accordance with the instructions for medical use.

For recommendations on dose reductions or interval extensions during chemotherapy based on blood counts, see Appendix A3.2.

For cHL patients aged 18 to 60 years who have completed planned polychemotherapy and whose treatment response was assessed solely by CT results, it is recommended to consider local radiation therapy to areas of residual tumor masses greater than 2.5 cm at a total cumulative dose (TCD) of 30 Gy [4, 37, 38].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For cHL patients aged 18 to 60 years who have completed planned polychemotherapy, it is recommended to consider local radiation therapy in patients with baseline extranodal involvement (bone, in exceptional cases — spleen, liver, etc.), depending on the response to medical treatment and the affected organ, at a dose of 30–36 Gy [4, 37, 38].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For patients older than 18 years with stage IV cHL confirmed immunohistochemically, for whom intensive first-line chemotherapy programs are indicated but cannot be administered or continued, or who are at high risk of bleomycin**-induced pneumonitis (such as a history of pneumonitis of any etiology, chronic lung diseases [COPD, severe asthma, etc.], a history of thoracic radiation therapy, marked decrease in pulmonary function tests, or a reaction to bleomycin** administration), as an alternative to the ABVD program that is more intensive than standard first-line therapy, the combination of brentuximab vedotin** with AVD chemotherapy — the BV-AVD regimen (for description of regimens, see Appendix A3.1) — may be recommended [39, 40].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2).

For cHL patients receiving the BV-AVD regimen as first-line therapy, primary G-CSF prophylaxis of neutropenia is recommended starting from the first cycle of chemotherapy [39].

GPR BLEL 2Grade of Recommendation B (Level of Evidence 2).

Comment: neutropenia prophylaxis should be initiated no later than day 5 after each administration of antineoplastic drugs according to the BV+AVD regimen, starting from the 1st administration, regardless of the leukocyte count on the day of administration (see Appendix A3.2).

3.3 First-line therapy for cHL in children and adolescents under 18 years of age

Therapy for children and adolescents under 18 years of age with verified HL begins immediately after diagnosis verification and staging. In the case of laparoscopy, therapy begins 5 days after surgery.

Concurrently with chemotherapy, the patient may receive hyperhydration with 2.5–3 L/m²/day of glucose-saline solutions (B05CB — salt solutions).

After every 2 cycles of chemotherapy, a follow-up examination is performed (see section "2. Diagnostics of the disease or condition (groups of diseases or conditions), medical indications and contraindications for the use of diagnostic methods" of these guidelines) — 10–14 days after the end of the cycle.

For treatment-naive patients under 18 years of age with IA/B or IIA stages of HL, polychemotherapy according to the OEPA regimen (2 cycles) is recommended (for description of regimens, see Appendix A3.1) [41, 42].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

For patients under 18 years of age with IA/B or IIA stages of HL who achieved a complete metabolic response (based on PET/CT results of 1–3 points on the Deauville scale) after 2 cycles of OEPA, 1 cycle of the COPDAC regimen is recommended (for description of regimens, see Appendix A3.1) followed by omission of radiation therapy [41, 42].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

For treatment-naive patients under 18 years of age with IEA/B, IIEA, IIB, or IIIA stages of HL, polychemotherapy according to the OEPA (2 cycles) + COPDAC (2 cycles) regimen is recommended (for description of regimens, see Appendix A3.1) [41, 42].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

For treatment-naive patients under 18 years of age with IIEB, IIIEA/B, IIIB, IVA/B stages of HL, polychemotherapy according to the OEPA (2 cycles) + COPDAC (4 cycles) regimen is recommended (for description of regimens, see Appendix A3.1) [41, 42].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

For patients under 18 years of age with HL who have a PET/CT-positive residual tumor after the 2nd block of PCT or a tumor volume reduction of less than 95% from baseline (in the absence of PET/CT data), radiation therapy to the initially affected lymphatic chains at a TCD of 19.8 Gy is recommended [43].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: if there are indications for radiation therapy in patients with Hodgkin lymphoma, it is necessary to irradiate all affected lymph nodes identified in the initial PET/CT scan performed before chemotherapy. When defining radiation volumes, ICRU 50/62 must be followed [44].

The minimum requirement for irradiation in children is 3D conformal radiation therapy. Radiation therapy should be delivered using a linear accelerator with photon energy of at least 6 MV, equipped with a multileaf collimator and a patient and/or target positioning verification system (cone-beam CT, portal imaging system, etc.). The use of electron beams with appropriate energy to irradiate superficially located lymph node groups, such as inguinal ones, is not excluded. Intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), TomoTherapy, and proton therapy can be used.

Radiation therapy for tumors in children should be performed using mechanical immobilization (individual thermoplastic mask, vacuum mattress for patient positioning). Provision should be made for the possibility of irradiation under general anesthesia for patients under 4 years of age and, clinically indicated, for older patients.

It is preferable to irradiate all involved areas simultaneously. In stage III–IV disease, the decision on sequential irradiation is made individually, with residual tumor masses or areas of initial extensive involvement being included in the radiation volume first. The interval between courses of radiation therapy should not exceed 2 weeks.

The gross tumor volume (GTV) includes the volume of affected lymph nodes. The clinical target volume (CTV) includes the GTV with a 1–2 cm safety margin, taking into account anatomical barriers to disease spread (usually within the anatomical boundaries of the region). The planning target volume (PTV₁) includes the CTV plus an institution-standard margin, usually 7–10 mm in all directions. For the mediastinum, para-aortic region, and pelvis, the CTV margin in the craniocaudal direction should be at least 2 cm. The hylar lymph nodes of the lungs are considered an independent region.

The total cumulative dose of irradiation is 19.8 Gy, with standard fractionation at a fractional dose of 1.8 Gy per fraction, 5 fractions per week. All fields are irradiated daily. A reduction of the fractional dose to 1.5–1.6 Gy is permissible for large irradiation volumes and/or in younger children.

The border of the planned radiation exposure is determined by the tumor size at the end of chemotherapy with an additional 1–2 cm margin.

Radiation therapy should be initiated in the 2nd to 4th week after completion of chemotherapy, i.e., on days 14–28 from the last dose of prednisolone**.

The issue of extranodal irradiation should be decided on an individual basis.

For patients under 18 years of age with HL and a residual tumor >100 cm³, as well as patients with a residual tumor >5 cm³and tumor regression ≤75% of the initial volume, additional irradiation at a TCD of 10 Gy (fractional dose 2 Gy) is recommended [43].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: the boost volume (PTV_boost) is determined by the size of the residual tumor with a 1 cm safety margin plus the institutional PTV margin (PTV_boost is determined using an algorithm similar to the PTV determination). At the same time, the borders of the PTV_boost volume must not extend beyond the borders of PTV₁.

For patients under 18 years of age with extranodal HL involvement or splenic involvement, RT is recommended depending on the affected organ [38]:

Spleen: the organ is considered involved if there is focal radiopharmaceutical uptake on the initial PET/CT or if there is evidence of focal changes on MRI or ultrasound. In this case, irradiation of the entire spleen is required, taking into account possible organ displacements, up to a TCD of 19.8 Gy. Diffuse radiopharmaceutical uptake in the spleen is not always considered involvement and should be discussed on an individual basis.
Lungs: an indication for lung irradiation is the persistence of residual lesions in the lung after two cycles of chemotherapy, identified on the initial PET/CT. In the presence of a solitary lesion of the organ after 2 cycles of PCT, the lesion is irradiated locally with a fractional dose of 1.8 Gy, TCD of 19.8 Gy. The CTV margin is 1 cm, plus an additional PTV margin. In the presence of two or more lesions, the organ is irradiated totally: in case of involvement of 1 lung, up to a TCD of 14–15 Gy (the unaffected lung is not irradiated), in case of involvement of both lungs, up to a TCD of 12 Gy, fractional dose 1–1.2 Gy.
Liver: an indication for liver irradiation is its primary involvement on PET/CT. In the presence of a solitary lesion in the liver, local radiation therapy at a TCD of 19.8 Gy must be performed. At the same time, a 1–2 cm safety margin and the PTV margin must be taken into account. If two or more lesions are detected, total liver irradiation must be performed, taking into account possible organ displacements, up to a TCD of 15 Gy with a fractional dose of 1–1.2 Gy.
Kidneys: an indication for kidney irradiation is its primary involvement, also recorded after 2 cycles of PCT on PET/CT. The organ is irradiated totally, taking into account possible organ displacements, up to a TCD of 12 Gy with a fractional dose of 1–1.2 Gy.
Bones: indication for irradiation of the skeletal bones is their primary involvement, also detected on CT or PET/CT after 2 courses of polychemotherapy. If 1–2 bone lesion sites are identified in a patient, they must be irradiated with a safety margin of 1–2 cm, accounting for an alignment error of up to a total dose (TD) of 19.8 Gy with a fractional dose (FD) of 1.8 Gy. In case of initial vertebral involvement, the entire vertebra should be included in the CTV with a subsequent 0.5 cm margin when generating the PTV. If more than two bone lesion sites are detected, the need for their irradiation is discussed on an individual basis.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Treatment-naive patients under 18 years of age with cHL presenting with tracheal compression and inferior vena cava syndrome, in the presence of anesthesia risks, should undergo surgical intervention followed by prolonged intubation; if this is not possible, it is recommended to use a prednisolone** pre-phase (in children over 3 years of age) at 30–60 mg/m² for 3–5 days prior to procedures performed under general anesthesia [45].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

3.4 First-line therapy for cHL in patients over 60 years of age

Treatment-naive patients older than 60 years with advanced stages of cHL are recommended an individualized choice of treatment regimen depending on the patient's comorbidities [4, 46, 47].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: the relative scarcity of individuals over 60 years of age in clinical trials (less than 10%) creates difficulties in proving the efficacy of certain treatment regimens and, accordingly, in selecting first-line therapy for these patients. Poor tolerance of the relative dose intensity of treatment approaching the adequately calculated value leads to a reduction in relative dose intensity to ≤65% of the planned level and to a significant shortening of both overall survival and progression-free survival.

The ABVD regimen — the "gold standard" — which is acceptable in terms of hematological toxicity and efficacy, carries a high risk of bleomycin**-induced pulmonary toxicity, the incidence of which in the ≥60 age group is 24%, with a treatment-related mortality of 18%. The use of intensive regimens in this age group is associated with a high risk of therapy-related mortality: when using the BEACOPP regimen at baseline doses, treatment-related mortality reaches 21%, whereas the omission of etoposide** — the BACOPP regimen — reduces this figure to 12%, which nevertheless remains an unacceptable risk for patients with HL. In two prospective studies demonstrating the efficacy of the VEPEMB regimen, toxicity-related mortality was 3% and 7%.

Pre-existing cardiac pathology and/or the risk of cardiac complications necessitate the use of regimens without anthracyclines and related compounds, such as ChlVPP, CVPP, COPP. It should be borne in mind that the therapeutic potential of the COPP/CVPP regimens is fully realized only provided that the patient receives at least 95% of the dose of each drug. The volume of radiotherapy to the mediastinal region should also be minimized. In cases combining cardiac and pulmonary pathology, an #idarubicin**-containing IVDG regimen may be used, which lacks bleomycin**, and the drug administration schedule allows for optimal control of myelotoxicity [48].

To reduce the risk of doxorubicin** cardiotoxic complications, the latter may be replaced with less cardiotoxic agents — #mitoxantrone** or #idarubicin** (based on the calculation: doxorubicin** 50 mg/m² — #mitoxantrone** or #idarubicin** 12 mg/m², doxorubicin** 25 mg/m² — #mitoxantrone** or #idarubicin** 5 mg/m²) [48, 157].

Furthermore, to minimize the risk of myelotoxic complications or in the presence of severe comorbidities, the CHOP-21 or CVP regimens may be used. In extreme cases, patients with severe contraindications to chemotherapy may be prescribed metronomic therapy such as PEPC or monotherapy with HL-active agents. The dosing frequency and duration of the course in this case will depend on efficacy and toxic complications. Vinblastine** 5.5 mg/m² IV once every 14 days, #etoposide** 50 mg/m² or #cyclophosphamide** 50–150 mg orally, in courses of 7–14 days, are used [4].

3.5 Selection of second- and subsequent-line therapy in patients with cHL

Patients aged 18 to 60 years with cHL from the low-risk group (early-stage HL without unfavorable prognostic factors) who received only 2 cycles of ABVD followed by involved-site radiotherapy as first-line therapy are recommended to consider 6 cycles of escalated BEACOPP (for regimen descriptions, see Appendix A3.1) [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Patients under 50 years of age with cHL in good performance status (ECOG 0–1, no severe comorbidities) with refractory disease (partial remission not achieved after completion of the chemotherapy phase, progression documented), or with first early relapse of cHL (remission duration less than 1 year after completion of induction treatment), or with first late relapse of cHL with high tumor burden or second late relapse, provided that prior treatment stages did not include irradiation of the lumbar spine and pelvic bones and/or cycles containing alkylating agents such as #melphalan** and lomustine**, are recommended to undergo a consultation at a transplantation center to address the feasibility of high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT), and, if feasible, to plan the regimens and timing of salvage therapy [4, 49].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: in isolated cases with very good general status and minimal comorbidity, following a thorough evaluation, HDCT with auto-HSCT may also be offered to patients aged 50 to 60 years for the same indications.

In pediatric practice, in case of disease progression or early relapse, a consultation at a transplantation center is required to address the feasibility of HDCT with auto-HSCT, and, if feasible, to plan the regimens and timing of salvage therapy.

In pediatric practice, treatment of late relapse (>12 months from the end of therapy) may involve 2nd-line chemotherapy regimens and re-irradiation.

Patients with cHL and refractory disease (partial remission not achieved after completion of the chemotherapy phase, progression documented), or with first early relapse of cHL (remission duration less than 1 year after completion of induction treatment), or with first late relapse of cHL and high tumor burden, or with second late relapse (if high-dose chemotherapy with auto-HSCT was not performed during the treatment of the first relapse), who are scheduled for HDCT with auto-HSCT, and if prior treatment stages did not include irradiation of the lumbar spine, pelvic bones, and/or did not utilize cycles containing alkylating agents such as #melphalan** and lomustine**, are recommended to undergo chemotherapy according to any second-line regimen chosen by the attending physician to determine tumor cell chemosensitivity, reduce tumor burden, and mobilize stem cells prior to the high-dose chemotherapy (HDCT) stage [49, 50].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: combinations such as ICE, DHAP, IGEV, BeGEV, GDP, ESHAP, GemOx, IEP, etc., may be used as second-line therapy (for regimen descriptions, see Appendix A3.1). Regimens incorporating brentuximab vedotin** and PD-1 inhibitors (L01XC: Monoclonal antibodies) (nivolumab**, pembrolizumab**) help increase the proportion of patients achieving a complete response prior to HDCT with auto-HSCT. The choice of second-line therapy regimen depends on the capabilities and preferences of the medical institution performing the treatment program (for regimen descriptions, see Appendix A3.1).

In pediatric practice, to achieve remission of cHL prior to HDCT with auto-HSCT, combination therapy using second-line drugs (#bendamustine**) and an immunoconjugate (L01XC: Monoclonal antibodies) (#brentuximab vedotin**) may be employed [160].

For patients with cHL and refractory disease (partial remission not achieved after the completion of the chemotherapy phase, progression documented), or with a first early relapse of cHL (remission duration of less than 1 year after completion of induction treatment), or with a first late relapse of cHL with high tumor burden or a second late relapse, who are candidates for HDT with auto-HSCT and in whom relapse chemotherapy has been initiated, provided that prior treatment stages did not include irradiation of the lumbar spine and pelvic bones and/or cycles involving alkylating agents such as #melphalan** and lomustine**, it is recommended to perform hemopoiesis stimulation with mobilization followed by the collection of hematopoietic stem cells (HSCs) for subsequent auto-HSCT (for a description of regimens, see Appendix A3.1) [51].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: the timing and regimen of HSC mobilization must comply with the recommendations of the transplantation center where auto-HSCT is planned.

For patients with cHL and refractory disease (partial remission not achieved after the completion of the chemotherapy phase, progression documented), or with a first early relapse of cHL (remission duration of less than 1 year after completion of induction treatment), or with a first late relapse of cHL with high tumor burden or a second late relapse, who are scheduled for HDT with auto-HSCT and have achieved complete PET-negative remission after relapse chemotherapy, provided that prior treatment stages did not include irradiation of the lumbar spine, pelvic bones, and sternum, and/or cycles involving alkylating agents such as #melphalan** and lomustine**, it is recommended to perform high-dose therapy using one of the conditioning regimens (for a description of regimens, see Appendix A3.1) followed by HSC transplantation [49, 50].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For patients with cHL and refractory disease (partial remission not achieved after the completion of the chemotherapy phase, progression documented), or with a first early relapse of cHL (remission duration of less than 1 year after completion of induction treatment), or with a first late relapse of cHL with high tumor burden or a second late relapse, who are scheduled for HDT with auto-HSCT and have not achieved complete PET-negative remission after cHL relapse chemotherapy, provided that prior treatment stages did not include irradiation of the lumbar spine and pelvic bones, and/or cycles involving alkylating agents such as #melphalan** and lomustine**, it is recommended to administer relapse therapy according to an alternative chemotherapy regimen to achieve PET-negative remission prior to high-dose therapy followed by HSC transplantation [52].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

For patients with immunohistochemically proven cHL who have undergone HDT with auto-HSCT and are at high risk of disease relapse or progression (resistance to first-line therapy, relapse or progression of lymphoma within 12 months after completion of first-line therapy, presence of extranodal involvement at relapse prior to HDT with auto-HSCT), upon recovery of hemopoiesis after HDT with auto-HSCT, it is recommended to administer consolidating therapy with #brentuximab vedotin** to target minimal residual disease (for a description of regimens, see Appendix A3.1) [53, 160, 165].

GCR ALEL 2Grade of Recommendation A (Level of Evidence 2) – for adults

GCR CLEL 4Grade of Recommendation C (Level of Evidence 4) – for children

Comment: consolidating therapy with brentuximab vedotin** is administered for a total of 16 cycles (infusions), with a follow-up evaluation after every 4 infusions.

For patients with relapsed or refractory cHL after one or more prior lines of therapy who are not candidates for HDT with auto-HSCT, it is recommended to administer therapy with pembrolizumab** (in patients older than 3 years) (for a description of the regimen, see Appendix A3.1) [56, 166, 171].

GCR BLEL 3Grade of Recommendation B (Level of Evidence 3) – for adults

GCR CLEL 5Grade of Recommendation C (Level of Evidence 5) – for children

For patients with cHL with relapsed or refractory disease after HDT with auto-HSCT, as well as those ineligible for HDT with auto-HSCT or with relapses after 2 or more prior lines of therapy, it is recommended to administer monotherapy with #brentuximab vedotin** (for a description of the regimen, see Appendix A3.1) [54, 165].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: upon confirmation of tumor sensitivity, at least 8 but no more than 16 cycles (infusions) of brentuximab vedotin** are administered with disease monitoring during treatment every 4 cycles. Following the completion of treatment, monitoring is performed in the standard manner.

For patients with cHL older than 18 years with relapsed or refractory disease after HDT with auto-HSCT and brentuximab vedotin**, or after three or more lines of systemic therapy including HDT with auto-HSCT, therapy with nivolumab** is recommended as one of the possible options (for a description of the regimen, see Appendix A3.1) [55].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: treatment with nivolumab** is carried out until disease progression or unacceptable toxicity. Indications for drug discontinuation are discussed individually in each clinical situation based on the results of evaluations performed every 6 months.

For patients with cHL with relapsed or refractory disease after HDT with auto-HSCT, it is recommended to administer therapy with nivolumab** (older than 18 years) or pembrolizumab** (older than 3 years) (for a description of the regimen, see Appendix A3.1) [55, 56, 166, 171].

GCR BLEL 3Grade of Recommendation B (Level of Evidence 3) – for pembrolizumab** in adult patients

GCR CLEL 4Grade of Recommendation C (Level of Evidence 4) – for nivolumab in adult patients

GCR CLEL 5Grade of Recommendation C (Level of Evidence 5) – for children

Comment: in pediatric practice, pembrolizumab** is used in children aged 3 years and older with relapsed or refractory cHL after HDT with auto-HSCT or after one or more prior lines of therapy in the presence of contraindications to HDT with auto-HSCT [166].

Treatment with nivolumab** or pembrolizumab** is carried out until disease progression or unacceptable toxicity. Indications for drug discontinuation are discussed individually in each clinical situation based on the results of evaluations performed every 6 months.

For patients with cHL with relapsed or refractory disease after HDT with auto-HSCT who have achieved complete or partial remission following the use of brentuximab vedotin** and/or immune checkpoint inhibitors (L01FF PD-1/PD-L1 (programmed cell death protein 1/death ligand 1) inhibitors) (nivolumab**, pembrolizumab**, etc.) or stabilization following the use of immune checkpoint inhibitors (L01FF PD-1/PD-L1 inhibitors), it is recommended to consult at a transplantation center to resolve the issue of the feasibility and possibility of allogeneic hematopoietic stem cell transplantation [57–59].

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

For patients with cHL who have exhausted transplantation, targeted therapy, and immunotherapy options, consideration of low-toxicity cytostatic therapy or radiation therapy at the discretion of the attending physician for palliative purposes may be recommended [4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: for palliative purposes, it is possible to use #gemcitabine**- (for patients older than 18 years) or lomustine**-containing regimens, #bendamustine** monotherapy, and/or local RT, which allows some patients to achieve sufficiently long disease remissions, a satisfactory quality of life, and good long-term survival rates. The choice of therapy for these patients is always individual. In patients with cytopenia, various metronomic regimens in combination with supportive care can be used for palliative purposes. This approach allows some patients to achieve a satisfactory quality of life even without achieving remission [4, 157].

Patients older than 18 years with cHL with multiple relapses and/or resistance to multiple lines of therapy, including auto-HSCT and targeted therapy, may be recommended the use for palliative purposes #nivolumab** at a fixed dose of 40 mg every 2 weeks or #pembrolizumab** at a fixed dose of 100 mg every 3 weeks [60, 61].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: the use of PD-1 inhibitors (L01XC: Monoclonal antibodies) allows some patients with cHL to achieve fairly long-term remissions, a satisfactory quality of life, and good long-term survival rates for this group of patients.

Patients older than 18 years with relapsed or refractory cHL who have not previously received RT and have achieved a complete metabolic response (Deauville score 1–3) after systemic relapse therapy may be recommended involved-site radiation therapy (ISRT) at doses of 30 Gy (in the absence of lesions) or 36 Gy (for residual PET-positive lesions >2.5 cm) [62].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Patients with relapsed or refractory cHL older than 18 years who are candidates for HDT with auto-HSCT and achieve a partial response after systemic relapse therapy may be recommended RT prior to transplantation to reduce the volume of target lesions: standard radiation dose is up to a total dose of 30–36 Gy (for large lesions — possibly up to a total dose of 40 Gy) [62].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

· Patients older than 18 years with cHL presenting with a late localized relapse in lymph nodes (no more than 3 adjacent small lesions) without B symptoms may be recommended RT alone with a total dose of 36–40 Gy [62].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: this option may be considered in patients with multiple prior lines of therapy, as well as in the presence of severe comorbidities, in elderly and advanced age. In case of localized relapse in patients who have previously received radiation therapy to the area encompassing the relapse site, local radiation therapy using modern 3D CRT technologies or proton therapy at a dose of 30–40 Gy may be performed, taking into account the volumes, doses, and timing of previously administered radiation therapy, as well as the radiation dose to organs at risk.

Patients with relapsed or refractory cHL who have achieved complete remission after relapse therapy but are not candidates for HDT with auto-HSCT may be recommended RT to all initial involved sites in the volume of ISRT 30–36 Gy [62, 167].

LeveL of Evidence CGrade of Recommendation 5Level of Evidence C (Grade of Recommendation 5) – for adults

GCR CLEL 4Grade of Recommendation C (Level of Evidence 4) – for children

Patients with relapsed or refractory cHL who have achieved a partial response after relapse therapy but are not candidates for HDT with auto-HSCT may be recommended RT exclusively to residual lesions at a total dose of 30–36 Gy. In patients older than 18 years with initially advanced disease, only relapse sites are irradiated (ISRT 30–36 Gy) with a possible dose escalation to large lesions up to a total dose of 40 Gy [62, 167].

LeveL of Evidence CGrade of Recommendation 5Level of Evidence C (Grade of Recommendation 5) – for adults

GCR CLEL 4Grade of Recommendation C (Level of Evidence 4) – for children

Patients with relapsed or refractory cHL who have contraindications to antitumor drug therapy may be recommended palliative RT at a total dose of up to 30–40 Gy [62, 167].

LeveL of Evidence CGrade of Recommendation 5Level of Evidence C (Grade of Recommendation 5) – for adults

GCR CLEL 4Grade of Recommendation C (Level of Evidence 4) – for children

3.6 Treatment of nodular lymphocyte-predominant Hodgkin lymphoma

The second type of HL in the revised 2017 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues is nodular lymphocyte-predominant Hodgkin lymphoma. NLPHL is a distinct, rare (incidence — 1.5 per 1 million) indolent lymphoma with a pathogenesis and immunophenotype different from cHL. NLPHL differs from cHL in its cellular composition (lymphohistiocytic cells), immunophenotype, clinical behavior, and, accordingly, treatment approach. The disease is most commonly diagnosed in men aged 20–40 years and responds fairly well to treatment. The prognosis of nodular lymphoma is favorable, although 3–5% of patients experience transformation into T-cell/histiocyte-rich large B-cell lymphoma or diffuse large B-cell lymphoma. Typically, the treatment of NLPHL follows the principle of therapeutic choice identical to cHL in all patients, except for those with stage IA without clinical risk factors. Treatment in early stages can even be carried out without the use of antitumor drugs, but with radiation therapy +/– #rituximab**. In case of relapse, a repeat biopsy is extremely necessary, as there is a probability of NLPHL transformation into diffuse large B-cell lymphoma / T-cell/histiocyte-rich large B-cell lymphoma.

Treatment-naive patients aged 18 years and older with stage IA NLPHL without bulky disease and other clinical risk factors are recommended local radiation therapy at a total dose of 30 Gy and/or #rituximab** monotherapy in the regimen for early stages of B-cell non-Hodgkin lymphomas (375 mg/m² once weekly for 4 weeks) [63–66].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: administration of single local RT is possible only subject to a thoroughly conducted modern initial staging evaluation using PET/CT.

Treatment-naive patients under 18 years of age with stage IA NLPHL without bulky disease and other clinical risk factors are recommended surgical resection of the lesion and active surveillance [67, 68].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Treatment-naive patients aged 18 years and older with stages IB–II NLPHL are recommended chemotherapy according to the ABVD or CHOP regimen (at the discretion of the attending physician) in combination with #rituximab** and radiation therapy at a total dose of 30 Gy to the initially involved areas [69, 70].

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

Comment: RT in patients with NLPHL is delivered to the sites of initially involved lymph nodes determined by PET/CT, with 2–5 cm margins. If PET/CT is not feasible prior to treatment, the RT volume is determined based on baseline ultrasound and CT data.

Treatment-naive patients under 18 years of age with stages IB–II NLPHL are recommended to undergo chemotherapy according to the CVP regimen with #rituximab** (for regimen descriptions, see Appendix A3.1) [71, 161, 162, 168, 169].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Treatment-naive patients with advanced (stages III–IV) NLPHL are recommended the use of the R-CHOP regimen (for regimen descriptions, see Appendix A3.1) [72, 168, 179, 183, 184, 191].

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

Treatment-naive patients older than 18 years with advanced (stages III–IV) NLPHL with bulky disease, extranodal involvement, and bone marrow involvement are recommended the use of the BEACOPPesc regimen as a standalone option or with #rituximab** (for regimen descriptions, see Appendix A3.1) [73, 74, 168].

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

Patients with relapsed or refractory NLPHL without signs of transformation into diffuse large B-cell lymphoma are recommended relapse therapy using chemotherapy regimens similar to those for cHL relapse, with the addition of #rituximab** (for regimen descriptions, see Appendix A3.1) [75].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Patients aged 18 years and older with relapsed or refractory stages I–II NLPHL without bulky disease and B symptoms, and without signs of transformation into diffuse large B-cell lymphoma, are recommended chemotherapy according to the RB program (#rituximab** + #bendamustine**) (for regimen descriptions, see Appendix A3.1) [76, 178].

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

Patients with recurrent NLPHL without signs of transformation into diffuse large B-cell lymphoma are recommended to have a consultation at a transplant center to address the possibility of HDT with autologous hematopoietic stem cell transplantation (auto-HSCT) [77, 78].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

3.7 Hodgkin lymphoma and pregnancy

Female patients with active HL who become pregnant, or in whom HL is diagnosed during pregnancy, are recommended a multidisciplinary team meeting including a hematologist and an obstetriciangynecologist for an individualized choice of patient management tactics [7, 79]. The diagnosis of HL must be morphologically verified; to determine the stage of the process, preference is given to ultrasound diagnostics and magnetic resonance imaging [7, 79].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: for any forms, degree of aggressiveness, and stages of HL, three management options are possible: pregnancy termination, watchful waiting, or initiation of antitumor therapy. The choice of tactics should be based on the following principles:

The combination of pregnancy and HL in remission is not an indication for pregnancy termination.
When HL is diagnosed in the II or III trimesters, combination chemotherapy during pregnancy is possible if necessary. It is desirable, if possible, to avoid chemotherapy regimens containing antimetabolites, high-dose alkylating agents, and #etoposide**. When administering chemotherapy, low-molecular-weight heparin (B01AB Heparin group) must be prescribed to prevent venous thromboembolic complications.
In cases of Hodgkin lymphoma diagnosed in the first trimester of pregnancy in women with favorable and intermediate prognosis (patients with stages IA and IIA without risk factors—massive mediastinal involvement or involvement of >4 lymph node areas), an expectant management approach and initiation of treatment in the second or third trimester of pregnancy is possible.
In patients with relapsed Hodgkin lymphoma, as well as in all women with newly diagnosed Hodgkin lymphoma with an unfavorable prognosis identified in the first trimester, pregnancy termination is indicated.
In all cases, the possibility of continuing pregnancy during active Hodgkin lymphoma, the timing of treatment initiation, and the choice of treatment regimens during pregnancy are decided exclusively by a hematologist or oncologist. In such situations, it is always essential to arrange delivery in perinatal centers or maternity hospitals equipped with a neonatal intensive care unit.
The timing of delivery must be determined jointly by obstetrician-gynecologists and oncologists or hematologists. When necessary, the fetus should be delivered at a time of maximum safety for its health (after 33–34 weeks of gestation) and the mother's health. Due to potential myelosuppression in both the mother and the fetus, polychemotherapy should be discontinued 3 weeks prior to the anticipated delivery date. The most favorable and safe method of delivery during polychemotherapy is vaginal delivery. Operative delivery should be performed according to obstetric indications.

Pregnant patients with Hodgkin lymphoma presenting with B symptoms, superior vena cava syndrome, or risk of disease progression are recommended to initiate single-agent chemotherapy with #vinblastine** 6 mg/m² (not exceeding 10 mg) every 10–14 days to stabilize the disease until delivery [7, 79].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: in pregnant patients with clinical symptoms of Hodgkin lymphoma resistant to single-agent #vinblastine** chemotherapy, the regimen of choice is ABVD (for regimen descriptions, see Appendix A3.1) [80]. Following delivery, a complete evaluation is performed, along with a treatment volume appropriate for the specific clinical situation, taking into account the therapy already received and its efficacy.

Pregnant patients with Hodgkin lymphoma are recommended to receive thromboprophylaxis throughout pregnancy and the postpartum period (6 weeks postpartum) [7].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: thromboprophylaxis should be selected individually based on relevant guidelines.

3.8 Response assessment

All patients with Hodgkin lymphoma, after 2 and 4 cycles of chemotherapy, after completing the chemotherapy phase, and after finishing the entire treatment program, are recommended an evaluation of treatment response in accordance with standard lymphoma response criteria to determine further management strategy (see section 7.5 of these guidelines) [1, 4, 81].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

3.9 Concomitant and supportive care

Patients with Hodgkin lymphoma presenting with bulky tumor involvement are recommended prophylaxis and treatment of tumor lysis syndrome: #allopurinol** 10 mg/kg/day and infusion therapy 3 L/m²/day with alkalinization using sodium bicarbonate** solution 40–80 mmol/L under the control of diuresis, planned administration of #furosemide** at a dose of 1–10 mg/kg, and laboratory monitoring of acid-base balance [82, 83, 153].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Patients with Hodgkin lymphoma receiving glucocorticoid therapy are recommended to undergo prophylaxis of gastric and duodenal ulcers [84].

GCR ALEL 1Grade of Recommendation A (Level of Evidence 1)

Comments: gastric or duodenal ulcer is one of the serious adverse effects of glucocorticoid therapy. The ulcerogenic mechanism of glucocorticoids involves increased hydrochloric acid secretion in the stomach, altered mucus composition, and inhibition of surface epithelial regeneration. Due to their ulcerogenic potential, antisecretory therapy must be administered when using glucocorticoids to prevent steroid ulcers.

Based on a meta-analysis of 300 studies [85], gastric and duodenal ulcers heal in virtually all cases if the intragastric pH is maintained above 3 for 18 hours per day. Considering this rule, current antiulcer therapy may include antacids, H2-receptor antagonists, and proton pump inhibitors (PPIs). According to one of the latest meta-analyses, the use of PPIs or H2-receptor antagonists achieves significantly more effective ulcer healing and reduces the risk of recurrent bleeding. Only these two classes of drugs allow for the achievement and maintenance of the required gastric pH environment necessary for the healing of gastroduodenal ulcers.

Currently, two classes of drugs are used for antisecretory purposes to prevent gastric and duodenal ulcers, including during glucocorticoid therapy: proton pump inhibitors and H2-receptor antagonists [86, 87].

Patients with Hodgkin lymphoma receiving anti-tumor chemo- or radiotherapy are recommended the use of antiemetic medications (5-HT3 receptor antagonists, NK-1 receptor antagonists (A04AD: Other antiemetics), gastrointestinal motility stimulants (metoclopramide**), anxiolytics, antipsychotics, proton pump inhibitors, H2-receptor antagonists) for the prevention of nausea and vomiting [88–90].
Level of recommendation C (level of evidence 5)

Comments: The choice of method for preventing nausea and vomiting is determined by the emetogenicity of the treatment regimen, individual threshold for nausea and vomiting, and comorbid conditions.

Patients with Hodgkin lymphoma undergoing chemoimmunotherapy regimens with a high risk of febrile neutropenia exceeding 20%, or an intermediate risk of febrile neutropenia of 10–20% in the presence of risk factors (age >65 years; severe comorbidities; renal or hepatic impairment; hemoglobin less than 12 g/dL; malnutrition; prolonged neutropenia or history of febrile neutropenia; lack of antimicrobial prophylaxis; ECOG ≥2; open wounds or wound infection; recent major surgery; female sex; chemoradiotherapy; cytopenia due to bone marrow involvement; HIV infection), are recommended primary prophylaxis of febrile neutropenia with G-CSF agents of the L03AA group according to the ATC classification [91].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: prophylactic administration of colony-stimulating factors (G-CSFs): filgrastim** 5 mcg/kg subcutaneously (s.c.) 24–72 hours after the completion of anti-tumor drug administration and until the recovery of a normal neutrophil count following the nadir, or for patients over 18 years of age, pegfilgrastim at a dose of 6 mg or empegfilgrastim** at a dose of 7.5 mg subcutaneously, as a single dose, no earlier than 24 hours after the completion of anti-tumor drug administration in accordance with the instructions for medical use, for the prevention and treatment of neutropenia induced by cytotoxic tumor chemotherapy.

Patients with Hodgkin lymphoma following a previously documented episode of febrile neutropenia or dose-limiting afebrile neutropenia (following a single episode of interval prolongation between cycles and/or dose reduction) are recommended secondary prophylaxis of febrile neutropenia with G-CSF agents of the L03AA group according to the ATC classification [91].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: prophylactic administration of colony-stimulating factor (G-CSF): filgrastim** 5 mcg/kg subcutaneously (s.c.) 24–72 hours after the completion of anti-tumor drug administration and until the recovery of a normal neutrophil count following the nadir, or for patients over 18 years of age, pegfilgrastim at a dose of 6 mg or empegfilgrastim** at a dose of 7.5 mg subcutaneously for patients over 18 years of age, as a single dose, no earlier than 24 hours after the completion of anti-tumor drug administration in accordance with the instructions for medical use, for the prevention and treatment of neutropenia induced by cytotoxic tumor chemotherapy.

Patients with Hodgkin lymphoma scheduled for intensive chemotherapy regimens are recommended to have a central venous catheter placed for chemotherapy and supportive care administration (see section 7.10) [92].
Strength of recommendation C (level of evidence 4).

Patients with Hodgkin lymphoma who have documented symptomatic hypogammaglobulinemia (prior severe infection, IgG <4 g/L) are recommended replacement therapy with normal human immunoglobulin** 0.2–0.4 g/kg IV every 3–4 weeks for 12 months to treat secondary immunodeficiency [93, 94].
Strength of recommendation C (level of evidence 5).

Comment: therapy is performed under the monitoring of IgG levels every 6 months, with a review of the normal human immunoglobulin** dose every 6 months. After completion of therapy, lifelong monitoring of IgG levels is performed once a year; in case of recurrent IgG drop <4 g/L, repeat courses of replacement therapy with a similar drug in a similar regimen are administered for 12 months.

Patients with HL and risk factors for thrombotic complications are recommended the use of anticoagulants (B01 Antithrombotic agents according to the ATC classification), physical methods of exposure (compression hosiery, limb pneumatic compression) for the prevention of venous thromboembolic complications [95, 96].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

In patients with HL receiving cytotoxic chemotherapy with the risk of developing or with developed oral or other gastrointestinal mucositis, it is recommended to use local and/or systemic analgesics (M01A: Non-steroidal anti-inflammatory and antirheumatic products (NSAIDs)), antidiarrheal agents (A07: Antidiarrheal, intestinal anti-inflammatory / anti-infective agents), synthetic somatostatin analogues (H01CB: Somatostatin and analogues), antibacterial and antifungal agents (J01: Antibacterials for systemic use, J02 Antimycotics for systemic use), antidepressants, glutamic acid preparations (A16AA Amino acids and derivatives) for prophylactic and therapeutic purposes; in severe cases, nasogastric tube placement [97, 98].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comments: the choice of method for the prevention and treatment of mucositis is determined by the severity and localization of the gastrointestinal mucosal lesion.

In patients with HL undergoing cytotoxic chemotherapy for the prevention of water-electrolyte disorders, it is recommended to provide nutritional support with parenteral trace element complexes, crystalline amino acid solutions, carbohydrate solutions, fat emulsions, ready-to-use balanced oral formulas (polymeric, oligomeric) depending on the type of nutritional disorder (V06D: Other nutrients, B05BA: Solutions for parenteral nutrition) [99, 100].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Women of childbearing potential with newly diagnosed HL scheduled for chemotherapy using intensive treatment regimens BEACOPP escalated, BEACOPP-14, EACOPP-14 are recommended an initial consultation (examination) with an obstetriciangynaecologist before starting treatment to discuss the choice of ovarian protection tactics [8].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

For patients of childbearing potential with HL, it is recommended to discuss the possibility of sperm or oocyte/embryo cryopreservation before starting therapy [101].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

For pediatric and young female HL patients in pediatric practice who are scheduled for pelvic radiotherapy, it is recommended to consider the need for homolateral oophoropexy for ovarian protection [102].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comment: oophoropexy is particularly indicated if the expected radiation dose to the ovaries exceeds 5 Gy, as this may lead to prolonged ovarian dysfunction. This can be avoided if radiotherapy is delivered via opposed fields to a total dose (TD) of 20 Gy and the ovary is located at least 2 cm away from the edge of the radiation field.

When performing an oophoropexy, the suture must be marked with a clip. The procedure is performed by a surgeon after consultation with a radiation oncologist prior to the start of subdiaphragmatic radiotherapy.

Patients with HL who develop acute or chronic pain syndrome are recommended to undergo diagnostics of the cause of the pain syndrome followed by pathogenetic or symptomatic therapy of the pain syndrome in accordance with current specialized guidelines [103, 104].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

All patients with HL at all stages of disease treatment, as well as after the completion of medical treatment, are recommended comprehensive rehabilitation and, if necessary, supportive care [105].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: there are no specific rehabilitation methods for HL. Rehabilitation of patients with HL should be comprehensive, covering not only medical but also social and psychological aspects of the patient's adaptation to normal life. Such rehabilitation requires, in addition to medical care, the mandatory participation of social workers and medical psychologists. Rehabilitation programs are developed individually, depending on the identified complications of medical treatment, comorbidities, and social and psychological problems.

Rehabilitation for complications arising during the course of the disease and treatment is carried out within the framework of the respective nosologies.

5. Prevention and Dispensary Observation

There are currently no methods for the prevention of HL, as the etiological factors leading to the development of the disease are unknown.

All patients with HL throughout their lives — both during and outside of treatment — are recommended to follow the prescriptions of the hematologist or oncologist regarding treatment, avoid factors provoking the disease, change the types and conditions of work to non-hazardous and lightened work, limit insolation and physiotherapeutic methods of treatment, and women of childbearing potential in complete remission of the disease should adhere to pregnancy planning tactics [4].

URC CLEL 5Level of Evidence C (Level of Certainty of Evidence 5).

Adult patients who have completed treatment for HL with the achievement of CR are recommended follow-up by an oncologist or hematologist during the first year after completion of therapy every 3 months, the 2nd year every 6 months, thereafter annually, and after 5 years every 2 years [1, 4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: follow-up should include careful collection of complaints, clinical examination of the patient, chest X-ray control, abdominal ultrasound (comprehensive), and peripheral lymph node basins. For patients who received anthracyclines (L01DB Anthracyclines and related substances) and bleomycin** in combination with mediastinal irradiation, cardiac and pulmonary function testing.

Children and adolescents who have completed treatment for HL with the achievement of CR are recommended follow-up by an oncologist or hematologist according to the schedule presented in Table 5.1 [45].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: Table 5.1. Schedule of follow-up for children after completion of therapy for HL (time from the end of radiation therapy)

Examination	1st year	2nd year	3rd year	4th year	5th year	6th year
visual therapeutic examination, therapeutic palpation, and therapeutic auscultation	4–8 times	4–8 times	4x	2x	2x	Individually
Complete (clinical) blood count with the study of hemoglobin, erythrocyte, platelet, leukocyte, and reticulocyte levels in the blood, differential leukocyte count (leukocyte formula) with assessment of the absolute leukocyte count, and erythrocyte sedimentation rate evaluation	4x	4x	2x	2x	2x
study of unforced respiratory volumes and flows (PFT)	1x	Individually
ultrasound examination of lymph nodes (ultrasound examination of lymph nodes (one anatomical zone)) and abdominal organs (comprehensive)	4x	4x	2x	2x	2x
Spiral CT of the neck/CT of the chest organs for stages I–II + CT of the abdominal organs/pelvic organs for stages III–IV, MRI	2x	2–1 times	1x	1x	1x
Thyroid-stimulating hormone (TSH) blood test Study of the level of total triiodothyronine (T3) in the blood, Study of the level of total thyroxine (T4) in blood serum	1x	1x	1x	1x	1x
Electrocardiogram recording / Echocardiography		1x			1x

All patients who achieved CR after treatment for HL, including radiation therapy to the cervical-supraclavicular lymph node regions, are recommended annual thyroid function testing (study of blood thyroid-stimulating hormone (TSH) level) and, if necessary, an initial consultation (examination) with an endocrinologist for 5 years [1, 4].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Children and adolescents who have completed treatment for HL with the achievement of CR are recommended screening for late effects of therapy (see Table 5.2), screening for organ complications of the administered treatment (see Table 5.3), and screening for cardiotoxic effects (depending on the administered treatment and the patient's age — see Table 5.4) [45].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment:

Table 5.2. Screening for late effects of anti-lymphoma therapy

1 year from the end of therapy (every 3 months)	• examination (height/weight, testicular volume, signs of puberty) (Initial consultation (examination) of a hematologist) • monthly breast self-examination • complete (clinical) blood count + erythrocyte sedimentation rate (ESR) test • Targeted chest X-ray / Spiral CT of the neck / CT of chest organs for stages I–II + CT of abdominal organs / pelvic organs for stages III–IV • ECG / echoCG / Holter heart rhythm monitoring, study of luteinizing and follicle-stimulating hormone levels in blood serum, study of total estradiol level in blood / study of total testosterone level in blood, study of total triiodothyronine (T3) level in blood, study of total thyroxine (T4) level in blood
2nd year from the end of therapy	• examination, tests, and CT every 6 months (Initial consultation (examination) of a hematologist) • annually — breast examination, assessment of heart, lung, and thyroid function, and hormonal status
3rd year from the end of therapy	examination, tests, and CT every 12 months (Initial consultation (examination) of a hematologist) • annually — breast examination, assessment of heart, lung, and thyroid function, and hormonal status
4th year from the end of therapy	Same
5th year from the end of therapy	Transition to follow-up care in the post-treatment surveillance service

Table 5.3. Screening for organ complications of administered treatment

Breast cancer	Self-examination monthly after puberty + clinical examination annually starting from puberty. Mammography 8 years after radiation therapy or starting from age 25.
Thyroid diseases	Patients after irradiation of 25 Gy and above are a risk group for the development of nodules and cancer, and after 20 Gy already, the risk of hypothyroidism. Annual examination and study of thyroid-stimulating hormone (TSH) and total thyroxine (T4) levels in blood serum for everyone.
Lung Diseases	Patients after chest irradiation and bleomycin** are a high-risk group. Baseline targeted chest radiography and assessment of unstimulated respiratory volumes and flows (pulmonary function testing) are recommended before any anesthesia and as needed (based on symptoms)
Other tumors	All individuals who received radiation therapy are at risk for skin cancer. Annual examination with a reminder about sun protection measures
Infertility or ovarian failure	The highest risk is in men who received 3 or more cycles with procarbazine, more than 7.5 g/m² cyclophosphamide, or pelvic/testicular irradiation Menarche usually occurs, but changes in luteinizing hormone, follicle-stimulating hormone, and estradiol levels may indicate immature ovarian function. Testosterone levels are rarely reduced in men, even if they are infertile and follicle-stimulating hormone is elevated

Table 5.4. Cardiotoxicity screening

Heart function
Age	Mediastinal irradiation	Dose of anthracyclines and related compounds	Echocardiography
< 1 year	+	any	annually
	–	< 200 mg/m²	every 2 years
	–	> 200 mg/m²	annually
1–4 years	+	any	annually
	–	< 100 mg/m²	every 5 years
		100–300 mg/m²	every 2 years
		> 300 mg/m²	annually
> 5 years	+	< 300 mg/m²	every 2 years
	+	> 300 mg/m²	annually
	–	< 200 mg/m²	every 5 years
		200–300 mg/m²	every 2 years
		> 300 mg/m²	annually

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting Public Health in the Russian Federation", is organized and provided:

in accordance with the regulations on the organization of the provision of medical care by types of medical care, which is approved by the authorized federal executive body;
in accordance with the clinical practice guidelines for hematology and oncology, which are mandatory for implementation by all medical organizations within the Russian Federation;
based on these clinical guidelines;
taking into account the standards of medical care approved by the authorized federal executive body.

Indications for planned hospitalization:

Initiation of specific therapy.
Planned continuation of specific therapy.
Diagnostic procedures that require inpatient conditions.

Indications for emergency hospitalization:

Complications of the underlying disease requiring specific inpatient treatment.
Life-threatening complications of specific therapy requiring appropriate inpatient treatment

Indications for patient discharge from the hospital:

Completion of specific therapy (in the absence of life-threatening complications of specific therapy).

The conclusion regarding the feasibility of transferring the patient to a specialized medical organization is drawn after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by medical specialists of the medical organization to which the transfer is planned.

7. Additional Information

7.1 General requirements for morphological diagnosis of Hodgkin lymphoma

Before lymph node biopsy, a complete blood count with differential must be performed to rule out biopsy in patients with chronic lymphocytic leukemia, monoclonal B-cell lymphocytosis, acute leukemias, or lymphocytosis of infectious (HIV, EBV, CMV infection, pertussis, viral hepatitis, toxoplasmosis, etc.) or other etiology (post-vaccination, drug reaction, smoking, thymoma, stress-induced lymphocytosis).

The diagnosis of Hodgkin lymphoma is established based on morphological and immunohistochemical examination of biopsy or surgical material. In some cases, molecular biological and genetic tests are required. Cytological examination of punctates or imprint smears from lymph nodes or other tumor sites is an auxiliary diagnostic method and cannot serve as a sufficient basis for the diagnosis of lymphoma and its nosological verification.

During the initial patient evaluation, histological and immunohistochemical examination of material from an excisional lymph node biopsy, an incisional/excisional biopsy of a pathological lesion, or surgical material must be performed in all cases, with the mandatory provision of an outpatient record/medical history summary to the pathologist. Puncturing lymph nodes for cell suspension aspiration is strictly discouraged. In exceptional cases (tumor location in hard-to-reach anatomical areas, severe patient condition) with documented justification in the medical records for the impossibility of performing an excisional biopsy, tissue material obtained via core-needle biopsy may be used. Suitable material is a biopsy specimen with a diameter of at least 16 G and a tumor infiltrate length in the tissue of at least 1.5 cm. The scope of the immunohistochemical study is determined by the pathologist during histological examination of the material. Splitting the material between different laboratories is strictly unacceptable. The morphological and immunohistochemical examination report must include:

Macroscopic description of the material submitted for examination; when examining prepared blocks and microslides, the report must indicate the quantity and identification numbers of all submitted objects.
Histological description of the lymphoma indicating the growth pattern (diffuse, nodular, etc.), characteristics of the cellular composition (small, large cells, polymorphic composition, anaplastic, blastic/blastoid morphology, presence of multinucleated forms, nuclear characteristics), and the presence of reactive and residual components. For the nodular sclerosis variant of classic Hodgkin lymphoma, a description of the presence, nature, and severity of the fibrous component and the cellular composition of the nodules is required. For nodular lymphocyte-predominant Hodgkin lymphoma, a description of the cellular composition of the nodules and an indication of the presence/absence of the fibrous component are required.
Results of the immunohistochemical examination indicating the antibodies used and staining details pointing to the specific nature of the reaction (e.g., nuclear staining in reactions with antibodies to TdT, BCL-6, Cyclin D1; cytoplasmic staining in reactions for CD79a; granular cytoplasmic reaction for cytotoxic molecules; cytoplasmic or membrane staining in reactions with antibodies to CD3, immunoglobulin heavy or light chains; membrane staining for CD20, CD10), intensity, and features of immunohistoarchitecture. Presenting immunohistochemical test results solely in the form of plus signs ("crosses") and a list of antibodies is unacceptable.
The pathomorphological conclusion, formulated in accordance with the current edition of the WHO classification of tumors of hematopoietic and lymphoid tissues (2017).

A mandatory component for determining the extent of the tumor process (staging) in patients who did not undergo PET-CT during initial diagnosis is a histological examination of a bone marrow trephine biopsy. Bilateral biopsy is recommended during the initial workup.

Morphological examination of bone marrow punctate (sternal or other) to rule out specific bone marrow involvement in classic Hodgkin lymphoma is not recommended because it is uninformative and does not replace a trephine biopsy.

Indications for trephine biopsy for classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma are described in section 2.5.

If the complete blood count or bone marrow cytological examination (myelogram) reveals lymphocytosis, regardless of the white blood cell count, as well as a predominance of lymphoid elements, atypical lymphocytes, or cells with blastic morphology in pleural, ascitic, or other biological fluids, flow cytometry immunophenotyping must be performed for the differential diagnosis of Hodgkin lymphoma versus other large-cell lymphomas. Flow cytometry allows for rapid differential diagnosis of neoplastic versus reactive lymphocytosis, which is important for determining the patient's further diagnostic and treatment strategy. Materials for flow cytometry analysis can include blood cells, bone marrow, effusion fluids, bronchoalveolar lavage, cerebrospinal fluid, homogenized tissue samples (spleen, lymph nodes, etc.), and cell suspensions obtained from fine-needle aspiration of lymph nodes.

When staging the tumor process, a biopsy of other affected sites may be required if their neoplastic nature cannot be ruled out by other means.

In the event of disease relapse or progression, repeat biopsy and morphological examination of affected lymph nodes or extranodal sites are strongly recommended. The biopsy should preferably be performed taking into account PET/CT results—from the lesion with maximum radiopharmaceutical uptake (fluorodeoxyglucose [18F]). Repeat biopsy is also indicated in the presence of residual masses to confirm remission, except for PET-negative residual masses in Hodgkin lymphoma. Performing a repeat biopsy of a pathological lesion is mandatory in cases of primary refractory disease or disease relapse to confirm the diagnosis or verify tumor transformation, as well as to rule out a second malignancy or infectious process.

Repeat bone marrow aspiration and trephine biopsy are performed for planned evaluation of treatment outcomes and upon the appearance of unexplained cytopenia and fever. Bone marrow aspirate may be informative for evaluating hematopoiesis regeneration and dysplastic changes.

7.2 Morphological and immunohistochemical diagnosis of HL

All variants of classic Hodgkin lymphoma are characterized by the same immunophenotype: CD30 (dot-like, membrane, cytoplasmic reaction), CD15 (dot-like, membrane, cytoplasmic reaction), PAX-5 (weak nuclear reaction compared to B-cells of the reactive microenvironment). Epstein-Barr virus (LMP1/EBER) may be detected in tumor cells.

CD15 expression is noted in approximately 85% of Hodgkin lymphoma cases, and PAX-5 in 95% of cases. In the absence of CD30 expression, the diagnosis of Hodgkin lymphoma is doubtful and requires advanced immunohistochemical investigation.

In some cases, tumor cells express the pan-B-cell marker CD20 (membrane reaction of heterogeneous intensity), CD19 (membrane reaction); expression of CD45 and CD3 by tumor cells is absent. An additional feature distinguishing Hodgkin lymphoma from diffuse large B-cell lymphoma is the absence of expression of CD79a, BCL-6, and the B-cell transcription factor BoB.1 (in some cases, a weak nuclear reaction is observed in individual tumor cells).

When establishing a diagnosis of classical Hodgkin lymphoma (HL), it is necessary to indicate the histological variant and immunophenotypic features (expression of CD20, EBV) (see Table 7.1.1). All cases of HL are subject to immunohistochemical verification.

Nodular lymphocyte-predominant Hodgkin lymphoma differs from classical HL in its clinical and immunomorphological characteristics. Tumor (LP) cells intensively express CD20, PAX-5, Oct-2, and other B-cell antigens, and are surrounded by rosettes of CD3+, CD57+, PD1+ T_FH lymphocytes. Expression of CD30 and CD15 on tumor cells is absent. In rare cases, aberrant immunophenotypic features of tumor cells are observed (e.g., weak expression or absence of BoB.1, Oct-2, Oct-3, CD79a, or PAX-5, or expression of CD30).

Table 7.2.1 WHO Morphological Classification of Hodgkin Lymphoma, 2017

Hodgkin lymphoma	Variants	Immunophenotype of the tumor substrate
Classical Hodgkin lymphoma	nodular sclerosis, types I and II; mixed cellularity; lymphocyte-rich; lymphocyte-depleted	CD30+, CD15+, CD20–/+ (expressed in 20-40% of cases), CD45–, PAX-5+ (weakly), BoB.1–, Oct-2– (or staining in a fraction of cells)
Nodular lymphocyte-predominant Hodgkin lymphoma		CD20+, CD45+, CD30– (expressed in isolated cases), CD15–, Oct-2+ (overexpressed), BoB.1+, BCL-6+, J-chain+

Hodgkin lymphoma

Variants

Immunophenotype of the tumor substrate

Classical Hodgkin lymphoma

nodular sclerosis, types I and II;

mixed cellularity;

lymphocyte-rich;

lymphocyte-depleted

CD30+, CD15+, CD20–/+ (expressed in 20-40% of cases), CD45–, PAX-5+ (weakly), BoB.1–, Oct-2– (or staining in a fraction of cells)

Nodular lymphocyte-predominant Hodgkin lymphoma

CD20+, CD45+, CD30– (expressed in isolated cases), CD15–, Oct-2+ (overexpressed), BoB.1+, BCL-6+, J-chain+

7.3 Staging and prognostic group determination in HL in patients over 18 years of age

Staging is performed based on the evaluation results in accordance with the Ann Arbor classification criteria (Cotswold modification) (Table 7.3.1).

Table 7.3.1 Ann Arbor Staging of Lymphomas, Cotswold Modification

7. Additional Information — Hodgkin Lymphoma

When staging lymphoma according to the Ann Arbor classification criteria, the concept of a "zone" is used — Fig. 7.3.1

Figure 7.3.1 Lymphatic drainage zones

Regardless of the stage, the general therapeutic approach involves dividing patients into two major groups:

group with limited disease volume (stages I and II, without bulky disease);
group with advanced disease (stages III or IV), which also includes patients with stage II and bulky disease. Bulky disease in stage II is considered limited or advanced depending on the presence or absence of certain risk factors.

The designation E for extranodal involvement is relevant only in two cases: to indicate limited extranodal involvement in the absence of lymph node involvement (IE), or in patients with stage II disease and direct extension of the tumor to tissues adjacent to the affected lymph nodes. The designation E, as well as the designation X (bulky), are not used in patients with advanced stage III or IV disease.

Table 7.3.2 Revised Staging System for Primary Nodal Lymphomas (Lugano, 2014) [106]

Upon completion of staging, the patient should be assigned to one of the prognostic groups: early stages with a favorable prognosis, early stages with an unfavorable prognosis, and advanced stages (Table 7.3.3) according to the criteria of the German Hodgkin Study Group (GHSG). In the group of patients with advanced stages, the International Prognostic Score (IPS; Table 7.3.4) may also be used to guide treatment selection.

Table 7.3.3 Prognostic Groups in Hodgkin Lymphoma for Patients Over 18 Years of Age

Algorithm for determining the prognostic group and selecting therapy according to GHSG criteria.

*In determining the prognostic group, the concept of "involvement area" is used, which may include several zones (Fig. 7.3.2):

a. right cervical + right supra-/subclavicular lymph nodes;

b. left cervical + left supra-/subclavicular lymph nodes;

c. right/left root lymph nodes + mediastinal lymph nodes;

d. right axillary lymph nodes;

e. left axillary lymph nodes;

f. upper abdominal lymph nodes (hepatic hilum, splenic hilum, celiac);

g. middle abdominal lymph nodes (para-aortic and mesenteric);

h. right iliac lymph nodes;

i. left iliac lymph nodes;

j. right inguinal + femoral lymph nodes;

k. left inguinal + femoral lymph nodes.

Figure 7.3.2 Lymphatic collection areas for determining the prognostic group according to the GHSG system

** ESR >30 mm/h for stage B and ESR >50 mm/h for stage A according to Panchenkov (>35 or >65 according to Westergren)

*** Mediastinal bulky lymph nodes — maximum tumor diameter greater than 1/3 of the maximum thoracic diameter on a plain chest X-ray or greater than 10 cm in maximum conglomerate diameter

Table 7.3.4 International Prognostic Score

International Prognostic Score (each factor = 1)
· Albumin <40 g/L · Hemoglobin <105 g/L · Male sex · Age ≥45 years · Stage IV · Leukocytosis ≥15 × 10⁹/L · Lymphopenia <8% on differential blood count or <0.6 × 10⁹/L

International Prognostic Score (each factor = 1)

· Albumin <40 g/L

· Hemoglobin <105 g/L

· Male sex

· Age ≥45 years

· Stage IV

· Leukocytosis ≥15 × 10⁹/L

· Lymphopenia <8% on differential blood count or <0.6 × 10⁹/L

7.4 Staging and prognostic group determination in HL in patients under 18 years of age

Based on risk factors, patients under 18 years of age are divided into therapeutic groups (Table 7.4.1):

Table 7.4.1 Definition of therapeutic groups (risk) for patients under 18 years of age.

7.5. 7.5. Response assessment in lymphomas

Response assessment to treatment is carried out in accordance with the updated criteria proposed by the International Working Group on Lymphoma in 2007 [81].

Complete remission (CR):

Complete disappearance of all evidence of disease, including findings detected by laboratory and imaging diagnostic methods, as well as clinical symptoms, if present before treatment initiation.
Lymph node dimensions:
a. ≤1.5 cm in greatest diameter, if pre-treatment lymph node dimensions were greater than 1.5 cm
b. ≤1.0 cm in greatest diameter, if pre-treatment lymph node dimensions were 1.5–1.1 cm
Liver and spleen, if involved and enlarged prior to treatment, are not palpable, and no mass lesions are detected in them by imaging modalities
Bone marrow with no evidence of tumor involvement. If the bone marrow morphological examination result is equivocal, the presence or absence of involvement must be determined immunohistochemically.

For HL, CR is considered confirmed if the achieved response persists for at least 3 months after the completion of the entire treatment program or if further improvement is documented.

Unconfirmed complete remission (CRu) is stated only in patients who did not undergo PET-CT for response assessment:

Residual abnormalities detected solely by imaging studies (particularly residual masses at the site of bulky tumor involvement, most commonly in the mediastinum), provided there is a reduction of the tumor by more than 75% of baseline sizes based on the sum of its two greatest diameters. These residual abnormalities must not increase in size for more than 3 months after completion of the entire treatment program.
Other parameters meet the criteria for complete remission.

Partial remission (PR):

A reduction in the sum of diameters of all measurable target lesions (lymph nodes and/or extranodal lesions) by at least 50%. If the dimensions of the involved lesions are less than 3 cm in greatest diameter, then the 2 largest lesions must decrease by at least 50% in greatest diameter. If there are more than 6 target lesions larger than 3 cm, evaluation of the 6 largest lesions clearly measurable in two perpendicular directions is sufficient. If mediastinal and/or retroperitoneal target lesions are present, they must be included in the measurements.
Absence of new lesions, no evidence of progression of any previously diagnosed lesions.
In cases of baseline bone marrow involvement, the bone marrow status is not significant for determining PR. However, if bone marrow involvement persists during and/or after completion of treatment, characterization of the tumor cells is mandatory. Patients with baseline bone marrow involvement who achieve clinical CR after treatment completion but have persistent bone marrow involvement or unevaluable bone marrow are classified as having PR.

Stable disease

Tumor parameters do not meet the criteria for CR, PR, or progression.

Relapse (after CR) or progression (after PR or stable disease)

Appearance of new lesions (enlarged lymph nodes or extranodal masses) greater than 1.5 cm in the greatest dimension during or after treatment completion, regardless of changes in the size of other lesions.
Increase of at least one previously known lesion by more than 25% from the minimum size. For lesions less than 1 cm in greatest dimension, an increase to 1.5 cm or more.

7.6. General principles of RT in patients with HL

Radiotherapy in primary HL patients is a component of combined immunochemoradiotherapy, used to consolidate remission achieved by drug therapy, with a curative intent. Radiotherapy parameters are determined based on the initial extent of the disease—lymph node involvement, presence and localization of extranodal sites, and residual tumor volume. The radiation volume is most commonly limited to the initially visualized lymph nodes and extranodal sites (involved sites). Identification of baseline lesions should be performed using computed tomography of the neck, chest, abdomen, and pelvis (with intravenous bolus contrast enhancement), and positron emission tomography combined with computed tomography using tumor-tropic radiopharmaceuticals like Fludeoxyglucose [18F]. These studies must also be performed after completion of medical therapy to determine the volume and dose of the upcoming irradiation. Modern planning technology (3D, 4D) allows for more precise determination of tumor borders and, accordingly, reduction of the treatment field sizes.

In early-stage lymphomas, when involvement is limited to lymph nodes and radiotherapy is used for remission consolidation, the involved-site radiotherapy (ISRT) volume is appropriate. If complete tumor regression is not achieved, additional focal irradiation of PET-positive tumor sites ("boost") may be used. During treatment planning, the medical physicist must calculate the dose-volume histogram and the normal tissue complication probability, which must be considered by the radiation oncologist when approving the final treatment plan.

Advanced RT techniques, such as intensity-modulated radiotherapy (IMRT), deep inspiration breath-hold radiotherapy, image-guided radiotherapy (IGRT), or proton therapy, demonstrate significant and clinically relevant advantages in reducing the dose load to organs at risk (such as the heart (including coronary arteries and valves), lungs, kidneys, spinal cord, esophagus, bone marrow, breasts, stomach, muscles, soft tissues, salivary glands) and reduce the risk of late normal tissue injury while simultaneously achieving the primary goal of treatment—local tumor control.

Achieving a highly conformal dose distribution is particularly important for patients undergoing curative radiotherapy or those with a long expected life expectancy following its completion. Thus, in mediastinal lymphoma, it is advisable to use 4D-CT for irradiation program planning and the deep inspiration breath-hold technique.

Performing high-precision radiotherapy requires precise target definition, margins for clinical and planning target volumes, and careful monitoring to avoid a "geographic miss". To ensure this quality assurance, periodic cone-beam computed tomography (CBCT) imaging may be required. When selecting irradiation programs, adherence to QUANTEC guidelines for normal tissue dose constraints is recommended.

External beam radiotherapy is preferably performed using a linear electron accelerator. The fractionation regimen is conventional—daily, 5 times a week, with a single fraction dose of 2.0 Gy and a total dose of 30–46 Gy depending on the clinical situation.

Radiotherapy should be initiated 4–5 weeks, but no later than 6 weeks, after the completion of immunochemotherapy or chemotherapy.

7.7. Special considerations for RT dose planning for critical structures in patients under 18 years of age.

Skeletal system.

Radiosensitivity is highest in young children (under 6 years) and during the prepubertal period (11–13 years). The dose to the growth plates of long bones should be limited (not exceeding 20 Gy). Asymmetrical irradiation of the axial skeleton can lead to kyphosis or scoliosis, whereas symmetrical irradiation leads to growth retardation. To avoid the development of scoliosis, irradiation of the entire spine within the PTV must be symmetrical. A dose gradient in the vertebral bodies exceeding 20% is unacceptable. [170]

Lungs.

Lung tolerance in children is poorly understood and appears not to differ significantly between adults and school-age children. The dose specified in these guidelines (12–15 Gy) for total lung irradiation is unlikely to cause significant deterioration in pulmonary function. Nevertheless, whole-lung irradiation at a dose of 12 Gy in children under 6 years of age may lead to a permanent reduction in vital capacity [170]

Heart.

Myocardial and arterial dysfunction may occur after a long latency period (20 years or more) as a late consequence of radiation-induced endothelial proliferation. There is no clear information on the effect of age at the time of irradiation. Cardiac irradiation should be minimized, especially in combination with cardiotoxic anthracyclines, which can reduce overall cardiac tolerance. Valve fibrosis and calcification, potentially leading to valvular heart disease, may occur. Therefore, the irradiated cardiac volume and cardiac dose should be kept to a minimum. Exceeding a heart dose of 30 Gy is not recommended. [170]

Breasts.

Late adverse deterministic effects on fully developed breasts are not expected. At the same time, undeveloped juvenile breasts are highly radiosensitive. Following irradiation of an undeveloped breast at a dose of 5 to 10 Gy, hypoplasia or aplasia of the entire breast or part of it may occur during adolescence. [170]

Thyroid gland.

Patients may develop subclinical hypothyroidism after a latency period of 3–4 years or more following irradiation of the gland at a dose of 20 Gy or greater. Subclinical hypothyroidism may resolve spontaneously, and the need for treatment in this case is controversial. The risk of thyroid dysfunction increases with radiation doses up to 30 Gy and may lead to clinical hypothyroidism requiring hormone replacement therapy. [170]

Testes.

The testes are the most radiosensitive organ. A dose of 1–2 Gy can lead to irreversible impairment of spermatogenesis. Therefore, the testes must be shielded during irradiation of the iliac and/or inguinal regions using modern irradiation techniques or by direct shielding. [170]

Ovaries.

Following a cumulative dose of 5–10 Gy, oocyte cell death is induced in the ovaries, leading to infertility. Endocrine failure occurs after higher doses are reached (approximately 10–15 Gy). In such cases, hormone replacement therapy may be required depending on the pubertal hormonal status. To avoid ovarian dysfunction, at least one ovary must be shielded from the effects of scattered radiation as well. Surgical transposition of the ovaries out of the proposed radiation fields (ovariopexy) is recommended. [170]

Secondary neoplasms

Radiation therapy in childhood increases the risk of developing a wide range of secondary tumors. The most common is breast cancer in women who underwent mediastinal and axillary radiation therapy in childhood. Therefore, regular breast cancer screening is recommended for women over 25 years of age or 8 years after radiation therapy. Irradiation of the cervical lymph nodes increases the risk of developing thyroid tumors, including malignant ones.

7.8. Infusion therapy in patients with Hodgkin lymphoma

For HL patients undergoing cytotoxic therapy, to prevent tumor lysis syndrome, in the event of dehydration, infectious, toxic, and hemorrhagic complications, or electrolyte disorders, infusion therapy is recommended [173].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

7.9. Use of donor blood components in patients with HL

For HL patients receiving cytotoxic chemotherapy, in the event of hemorrhagic or infectious complications, anemia, or thrombocytopenia induced by intensive chemotherapy, or with a therapeutic intent in patients with pre-existing hemorrhagic complications, and when performing various procedures (trephine biopsy, lumbar puncture, central venous catheter placement, etc.) under conditions of thrombocytopenia, replacement transfusion therapy with platelet concentrate, red blood cell suspension, fresh frozen plasma (FFP), blood coagulation factor VIII (ATX code B02BD), protease inhibitors, and antifibrinolytic agents (ATX code B02A) is recommended [174].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Medical indications for the use of donor blood components can be established both in patients with newly diagnosed disease and in patients with relapsed/refractory HL.

In patients with newly diagnosed disease, transfusions of donor blood components are most commonly performed during intensive first-line chemotherapy regimens (BEACOPP-escalated, BEACOPP-14, or EACOPP-14). In relapsed/refractory HL, donor blood components are primarily used during pre-transplant chemotherapy and following autologous or allogeneic transplantation.

In hematological diseases with known indications for repeated blood component transfusions (leukemias, lymphomas, myelodysplastic syndromes, aplastic anemia, etc.), blood components with the following characteristics may be used to prevent transfusion-related adverse reactions and complications:

leukoreduced — the leukocyte content in the transfused medium dose is reduced to 1 × 10^6 cells;
irradiated red blood cells and platelets (gamma irradiation or X-ray irradiation at a dose of 25–50 Gy)$
limitation of donor plasma use through the application of additive solutions for red blood cells;
following donor blood testing for viral infection markers using molecular biological methods

7.10. Vascular access management in patients with HL

For patients with Hodgkin lymphoma undergoing cytotoxic chemotherapy, in the event of toxic and infectious complications, electrolyte disturbances, or when supportive blood transfusion therapy, blood sampling, etc. are necessary, vascular access is recommended [175].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

7.11. Management of a patient with HL in the intensive care unit

At various stages of treatment, patients with Hodgkin lymphoma may develop critical conditions requiring admission to the intensive care unit (ICU). Critical syndromes requiring ICU admission include: sepsis, septic shock (SS), acute respiratory failure (ARF), acute kidney injury (AKI), ischemic or hemorrhagic acute cerebrovascular accident (stroke), life-threatening cardiac arrhythmias, and massive gastrointestinal bleeding. In very rare cases, the treatment of newly diagnosed Hodgkin lymphoma may be complicated by tumor lysis syndrome, accompanied by acute renal failure, metabolic disorders, and acute respiratory failure.

To treat life-threatening complications in patients with Hodgkin lymphoma in the ICU, life-support methods are most commonly used, including mechanical ventilation, vasopressor therapy, and renal replacement therapy [176, 177].

[1] Lymphatic structures include lymph nodes, spleen, thymus, Waldeyer's ring, appendix, and Peyer's patches.

[2] In Hodgkin lymphoma, stage II requires an additional Arabic numeral indicating the number of affected lymphatic regions (Fig. 7.3.1) (e.g., stage II₄).

[3] The mediastinum is considered a single lymphatic region, while bronchopulmonary lymph nodes are considered separate lymphatic regions (specification per Cotswold modification).

[4] It is recommended to distinguish stage III₁, with involvement of upper abdominal lymph nodes (hepatic, splenic, and celiac lymph nodes), and stage III₂, with involvement of retroperitoneal lymph nodes.

[5] Pruritus is excluded from B symptoms.

[6] The designation of bulky disease (X) and localized extranodal involvement (E) is relevant only for localized stages I and II, as it determines the selection of more intensive therapy.

[7] The designation of bulky disease (X) and localized extranodal involvement (E) is relevant only for localized stages I and II, as it determines the selection of more intensive therapy.

[8] The mediastinal-thoracic ratio is the ratio of the maximum width of the mediastinal shadow to the maximum thoracic diameter at the Th5–6 level on standard posteroanterior chest radiographs.

Criteria for Evaluating the Quality of Medical Care

№	Quality criteria	Performance evaluation
1.	In a patient with suspected or confirmed Hodgkin lymphoma, at the initial or follow-up visit, before the start of each new treatment cycle, during remission assessment after therapy completion, at follow-up evaluations, and upon suspicion of disease relapse, a complete blood count (CBC) must be performed, including hemoglobin, red blood cells, platelets, white blood cells, reticulocytes, differential white blood cell count with absolute leukocyte counts, and erythrocyte sedimentation rate (ESR).	Yes/No
2.	In a patient with suspected or confirmed Hodgkin lymphoma, at the initial or follow-up visit, before the start of each new treatment cycle, during remission assessment after therapy completion, at follow-up evaluations, and upon suspicion of disease relapse, a general biochemical blood test must be performed, including the following parameters: blood lactate dehydrogenase (LDH) activity, blood urea level, blood creatinine level, blood glucose level, total blood protein level, blood albumin level, total blood bilirubin level, blood aspartate aminotransferase (AST) activity, blood alanine aminotransferase (ALT) activity, blood alkaline phosphatase (ALP) activity, blood potassium level, blood sodium level, blood chloride level, and total blood calcium level.	Yes/No
3.	In a patient with newly diagnosed Hodgkin lymphoma, during treatment response assessment, or upon suspicion of disease relapse, computed tomography (CT) of the neck, chest, abdomen, and pelvis (with intravenous bolus contrast enhancement) must be performed, or (if CT contraindications or technical limitations exist) targeted two-view chest radiography, ultrasound examination of the lymph nodes (ultrasound examination of lymph nodes (one anatomical region)), and comprehensive abdominal ultrasound.	Yes/No
4.	A patient with suspected Hodgkin lymphoma must undergo a biopsy (obtaining biopsy material) of a lymph node or other lesion site, with histopathological examination of the biopsy (surgical) specimen using immunohistochemical methods to verify the diagnosis.	Yes/No
5.	A patient with Hodgkin lymphoma must undergo treatment response assessment in accordance with standard lymphoma response criteria after 2 and 4 cycles of chemotherapy, upon completion of the chemotherapy phase, and after the entire treatment program is finished.	Yes/No

References

Show references

1. Demin EA, et al. General principles of lymphoma diagnosis. In: Poddubnaya IV, Savchenko VG, eds. Russian Clinical Guidelines for the Diagnosis and Treatment of Malignant Lymphoproliferative Disorders. 2018:9–27.

2. Malignant tumors in Russia in 2017 (morbidity and mortality). Kaprin AD, Starinsky VV, Petrova GV, eds. Moscow: P. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health; 2018.

3. Swerdlow S.H. et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon, France: International Agency for Research in Cancer (IARC) / ed. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H T.J. 2017. 585 p.

4. Demin EA, et al. Hodgkin lymphoma. In: Poddubnaya IV, Savchenko VG, eds. Russian Clinical Guidelines for the Diagnosis and Treatment of Malignant Lymphoproliferative Disorders. 2018:28–43.

5. Kennedy-Nasser A.A., Hanley P., Bollard C.M. Hodgkin disease and the role of the immune system // Pediatric Hematology and Oncology. NIH Public Access, 2011. Vol. 28, № 3. P. 176–186.

6. Good R.A. Relations between immunity and malignancy. // Proceedings of the National Academy of Sciences of the United States of America. 1972. Vol. 69, № 4. P. 1026–1032.

7. Shmakov RG, Demin EA. Lymphomas and pregnancy. In: Poddubnaya IV, Savchenko VG, eds. Russian Clinical Guidelines for the Diagnosis and Treatment of Malignant Lymphoproliferative Disorders. 2018:143–150.

8. Demin EA, et al. Optimization of first-line therapy in patients with advanced stages of Hodgkin lymphoma: efficacy and toxicity of the intensive EACOPP-14 regimen (experience of the National Medical Research Center of Oncology named after N.N. Blokhin of the Russian Ministry of Health). Clinical Oncohematology. Fundamental Research and Clinical Practice. 2017;10(4):443–452.

9. Eichenauer D.A. et al. Hodgkin lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up // Ann Oncol. Ann Oncol, 2018. Vol. 29, № Suppl 4. P. iv19–iv29.

10. Sieniawski M. et al. Fertility in male patients with advanced Hodgkin lymphoma treated with BEACOPP: A report of the German Hodgkin Study Group (GHSG) // Blood. 2008. Vol. 111, № 1. P. 71–76.

11. Vinokurov AA. Hodgkin lymphoma and reproductive issues in men. Clinical Oncohematology. 2013;6(3):258–273.

12. Kanoun S., Rossi C., Casasnovas O. [18F]FDG-PET/CT in hodgkin lymphoma: Current usefulness and perspectives // Cancers. 2018.

13. Gallamini A. et al. Early Chemotherapy Intensification With Escalated BEACOPP in Patients With Advanced-Stage Hodgkin Lymphoma With a Positive Interim Positron Emission Tomography/Computed Tomography Scan After Two ABVD Cycles: Long-Term Results of the GITIL/FIL HD 0607 Tria // J Clin Oncol. 2018. Vol. 36, № 5. P. 454–462.

14. Johnson P. et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma // New England Journal of Medicine. Massachusetts Medical Society, 2016. Vol. 374, № 25. P. 2419–2429.

15. Borchmann P. et al. PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group // Lancet. Lancet, 2017. Vol. 390, № 10114. P. 2790–2802.

16. Casasnovas R.O. et al. PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study // Lancet Oncol. Lancet Oncol, 2019. Vol. 20, № 2. P. 202–215.

17. Yokoyama K. Thrombosis in lymphoma patients and in myeloma patients // Keio Journal of Medicine. Keio University School of Medicine, 2015. Vol. 64, № 3. P. 37–43.

18. Krivolapov YuA, Leenman EE. Morphological diagnosis of lymphomas. KOSTA, Saint Petersburg; 2006.

19. Adams H.J.A., Nievelstein R.A.J., Kwee T.C. Opportunities and limitations of bone marrow biopsy and bone marrow FDG-PET in lymphoma // Blood Rev. Churchill Livingstone, 2015. Vol. 29, № 6. P. 417–425.

20. Voltin C.-A. et al. Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18 // Annals of Oncology. 2018. Vol. 29, № 9. P. 1926–1931.

21. Moiseeva TN, Al-Radi LS, Dorokhina EI. Protocol for the diagnosis and treatment of classical Hodgkin lymphoma. In: Savchenko VG, ed. Diagnostic Algorithms and Treatment Protocols for Hematopoietic Diseases. National Medical Research Center for Hematology. 2018:39–56.

22. Engert A. et al. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin’s lymphoma: Final results of the GHSG HD7 trial // Journal of Clinical Oncology. 2007.

23. Meyer R.M. et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma // New England Journal of Medicine. 2012.

24. Baues C. et al. Involved-Field Radiation Therapy Prevents Recurrences in the Early Stages of Hodgkin Lymphoma in PET-Negative Patients After ABVD Chemotherapy: Relapse Analysis of GHSG Phase 3 HD16 Trial // Int J Radiat Oncol Biol Phys. Int J Radiat Oncol Biol Phys, 2021. Vol. 111, № 4. P. 900–906.

25. Allen P.B., Gordon L.I. Frontline Therapy for Classical Hodgkin Lymphoma by Stage and Prognostic Factors // Clinical Medicine Insights: Oncology. SAGE Publications Ltd, 2017. Vol. 11.

26. Skoetz N. et al. Comparison of first-line chemotherapy including escalated BEACOPP versus chemotherapy including ABVD for people with early unfavourable or advanced stage Hodgkin lymphoma // Cochrane Database of Systematic Reviews. 2017.

27. Von Tresckow B. et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: Final analysis of the German Hodgkin study group HD14 trial // Journal of Clinical Oncology. 2012. Vol. 30, № 9. P. 907–913.

28. Hoppe B.S. et al. Effective dose reduction to cardiac structures using protons compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma // Int J Radiat Oncol Biol Phys. 2012. Vol. 84, № 2. P. 449–455.

29. Hoppe B.S. et al. Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma // Annals of Oncology. 2017. Vol. 28, № 9. P. 2179–2184.

30. Tseng Y.D. et al. Evidence-based Review on the Use of Proton Therapy in Lymphoma From the Particle Therapy Cooperative Group (PTCOG) Lymphoma Subcommittee // International Journal of Radiation Oncology Biology Physics. Elsevier Inc., 2017. Vol. 99, № 4. P. 825–842.

31. Engert A. et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. // Lancet. 2012. Vol. 379, № 9828. P. 1791–1799.

32. Sieber M. et al. 14-Day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin’s lymphoma: Results of a pilot study of the German Hodgkin’s Lymphoma Study Group // Journal of Clinical Oncology. 2003. Vol. 21, № 9. P. 1734–1739.

33. Gallamini A. et al. Consolidation radiotherapy could be omitted in advanced Hodgkin lymphoma with large nodal mass in complete metabolic response after ABVD. Final analysis of the randomized HD0607 trial // Hematol Oncol. Wiley, 2019. Vol. 37. P. 147–148.

34. Barrington S.F. et al. PET-CT for staging and early response: Results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study // Blood. American Society of Hematology, 2016. Vol. 127, № 12. P. 1531–1538.

35. Wedgwood A., Younes A. Prophylactic use of filgrastim with ABVD and BEACOPP chemotherapy regimens for Hodgkin lymphoma. // Clin Lymphoma Myeloma. 2007. Vol. 8 Suppl 2. P. S63-6.

36. Engel C. et al. Acute hematologic toxicity and practicability of dose-intensified BEACOPP chemotherapy for advanced stage Hodgkin’s disease. German Hodgkin’s Lymphoma Study Group (GHSG). // Ann Oncol. 2000. Vol. 11, № 9. P. 1105–1114.

37. Hoppe R.T. et al. Hodgkin Lymphoma. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Version 1.2023. 2022. 95 p.

38. Yahalom J. et al. Modern radiation therapy for extranodal lymphomas: Field and dose guidelines from the international lymphoma radiation oncology group // Int J Radiat Oncol Biol Phys. Elsevier Inc., 2015. Vol. 92, № 1. P. 11–31.

39. Connors J.M. et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma // New England Journal of Medicine. N Engl J Med, 2018. Vol. 378, № 4. P. 331–344.

40. Ansell S.M. et al. Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma // N Engl J Med. N Engl J Med, 2022. Vol. 387, № 4. P. 310–320.

41. Mauz-Körholz C. et al. Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin’s lymphoma: The GPOH-HD-2002 study // Journal of Clinical Oncology. 2010. Vol. 28, № 23. P. 3680–3686.

42. Dörffel W. et al. Treatment of children and adolescents with hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95 // Journal of Clinical Oncology. 2013. Vol. 31, № 12. P. 1562–1568.

43. Hudson M.M., Constine L.S. Refining the role of radiation therapy in pediatric hodgkin lymphoma. // American Society Of Clinical Oncology Educational Book / ASCO. American Society Of Clinical Oncology. Meeting. From the Department of Oncology, Division of Cancer Survivorship, St. Jude’s Children’s Research Hospital, Memphis, TN; Departments of Radiation Oncology and Pediatrics, Philip Rubin Center for Cancer Survivorship, James P. Wilmot Cancer Center at Univers: American Society of Clinical Oncology, 2012. P. 616–620.

44. International Commission on Radiation Units and Measurments. Prescribing, Recording, and Reporting Photon Beam Therapy (Supplement to ICRU Report 50). 1999. 1–62 p.

45. Rumyantsev AG, Samochatova EV. Practical Guide to Pediatric Diseases. Vol. 4. Pediatric Hematology and Oncology. Kokolina VF, Rumyantsev AG, eds. Medpraktika-M; 2004. 792 p.

46. Borchmann S., Engert A., Böll B. Hodgkin lymphoma in elderly patients // Current Opinion in Oncology. Lippincott Williams and Wilkins, 2018. Vol. 30, № 5. P. 308–316.

47. Thyss A. et al. Hodgkin’s lymphoma in older patients: An orphan disease? // Mediterranean Journal of Hematology and Infectious Diseases. Universita Cattolica del Sacro Cuore, 2014. Vol. 6, № 1. P. 1–10.

48. Kaplanov KD, et al. The IVDG regimen as a potential first-line therapy option for Hodgkin lymphoma in elderly patients with concomitant cardiovascular and pulmonary diseases. Clinical Oncohematology. 2017;10(3):358–365.

49. Fedele R. et al. Clinical Options in Relapsed or Refractory Hodgkin Lymphoma: An Updated Review. // J Immunol Res. 2015. Vol. 2015. P. 968212.

50. Nikolaenko L., Chen R., Herrera A.F. Current strategies for salvage treatment for relapsed classical Hodgkin lymphoma. // Ther Adv Hematol. 2017. Vol. 8, № 10. P. 293–302.

51. Mohty M. et al. Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: A position statement from the European Group for Blood and Marrow Transplantation // Bone Marrow Transplantation. 2014.

52. Moskowitz A.J. et al. Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. // Blood. 2010. Vol. 116, № 23. P. 4934–4937.

53. Moskowitz C.H. et al. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. // Blood. 2018. Vol. 132, № 25. P. 2639–2642.

54. Chen R. et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. // Blood. 2016. Vol. 128, № 12. P. 1562–1566.

55. Younes A. et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. // Lancet Oncol. 2016. Vol. 17, № 9. P. 1283–1294.

56. Chen R. et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087 // Blood. American Society of Hematology, 2019. Vol. 134, № 14. P. 1144–1153.

57. Rashidi A., Ebadi M., Cashen A.F. Allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma: a systematic review and meta-analysis. // Bone Marrow Transplant. 2016. Vol. 51, № 4. P. 521–528.

58. Peggs K.S. Should all patients with Hodgkin lymphoma who relapse after autologous SCT be considered for allogeneic SCT? // Blood Adv. American Society of Hematology, 2018. Vol. 2, № 7. P. 817–820.

59. Mussetti A. et al. Synchronizing the use of allogeneic hematopoietic cell transplantation in checkpoint blockade therapy for Hodgkin lymphoma // Expert Rev Hematol. Expert Rev Hematol, 2021. Vol. 14, № 9. P. 809–818.

60. Lepik K. V. et al. A Phase 2 Study of Nivolumab Using a Fixed Dose of 40 mg (Nivo40) in Patients With Relapsed/Refractory Hodgkin Lymphoma // Hemasphere. Hemasphere, 2020. Vol. 4, № 5. P. e480.

61. Chan T.S.Y. et al. Low-dose pembrolizumab and nivolumab were efficacious and safe in relapsed and refractory classical Hodgkin lymphoma: Experience in a resource-constrained setting // Hematol Oncol. Hematol Oncol, 2020. Vol. 38, № 5. P. 726–736.

62. Constine L.S. et al. The Role of Radiation Therapy in Patients With Relapsed or Refractory Hodgkin Lymphoma: Guidelines From the International Lymphoma Radiation Oncology Group // International Journal of Radiation Oncology*Biology*Physics. 2018. Vol. 100, № 5. P. 1100–1118.

63. Wirth A. et al. Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma: a retrospective multicenter study of the Australasian Radiation Oncology Lymphoma Group. // Cancer. 2005. Vol. 104, № 6. P. 1221–1229.

64. Nogová L. et al. Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin’s lymphoma: a retrospective analysis from the German Hodgkin Study Group (GHSG). // Ann Oncol. 2005. Vol. 16, № 10. P. 1683–1687.

65. Eichenauer D.A. et al. Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocytepredominant Hodgkin lymphoma: A report from the German Hodgkin Study Group // Blood. 2011. Vol. 118, № 16. P. 4363–4365.

66. Nogová L. et al. Lymphocyte-predominant and classical Hodgkin’s lymphoma: a comprehensive analysis from the German Hodgkin Study Group // J Clin Oncol. J Clin Oncol, 2008. Vol. 26, № 3. P. 434–439.

67. Appel B.E. et al. Minimal treatment of low-risk, pediatric lymphocyte-predominant hodgkin lymphoma: A report from the children’s oncology group // Journal of Clinical Oncology. American Society of Clinical Oncology, 2016. Vol. 34, № 20. P. 2372–2379.

68. Mauz-Körholz C. et al. Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma // Cancer. 2007. Vol. 110, № 1. P. 179–185.

69. Cencini E., Fabbri A., Bocchia M. Rituximab plus ABVD in newly diagnosed nodular lymphocyte-predominant Hodgkin lymphoma // Br J Haematol. Blackwell Publishing Ltd, 2017. Vol. 176, № 5. P. 831–833.

70. Fanale M.A. et al. Outcomes of Nodular Lymphocyte Predominant Hodgkin’s Lymphoma (NLPHL) Patients Treated with R-CHOP. // Blood. Content Repository Only!, 2010. Vol. 116, № 21. P. 2812.

71. Shankar A. et al. Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin’s lymphoma - An Anglo-French collaborative report // Eur J Cancer. 2012. Vol. 48, № 11. P. 1700–1706.

72. Fanale M.A. et al. Encouraging activity for R-CHOP in advanced stage nodular lymphocyte–predominant Hodgkin lymphoma // Blood. 2017.

73. Eichenauer D.A. et al. Long-Term Follow-Up of Patients With Nodular Lymphocyte-Predominant Hodgkin Lymphoma Treated in the HD7 to HD15 Trials: A Report From the German Hodgkin Study Group // J Clin Oncol. J Clin Oncol, 2020. Vol. 38, № 7. P. 698–705.

74. Borchmann P. et al. Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin’s lymphoma treated with BEACOPP escalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group // Lancet Oncol. Lancet Oncol, 2017. Vol. 18, № 4. P. 454–463.

75. Advani R.H., Hoppe R.T. How i treat nodular lymphocyte predominant Hodgkin lymphoma // Blood. 2013. Vol. 122, № 26. P. 4182–4188.

76. Prusila R.E.I. et al. R-Bendamustine in the treatment of nodular lymphocyte-predominant Hodgkin lymphoma // Acta Oncol. Acta Oncol, 2018. Vol. 57, № 9. P. 1265–1267.

77. Eichenauer D.A. et al. Relapsed and refractory nodular lymphocyte-predominant Hodgkin lymphoma: An analysis from the German Hodgkin Study Group // Blood. American Society of Hematology, 2018. Vol. 132, № 14. P. 1519–1525.

78. Eichenauer D.A., Engert A. Nodular lymphocyte-predominant Hodgkin lymphoma: A unique disease deserving unique management // Hematology. American Society of Hematology, 2017. Vol. 2017, № 1. P. 324–328.

79. Bachanova V., Connors J.M. Hodgkin lymphoma in pregnancy // Curr Hematol Malig Rep. NIH Public Access, 2013. Vol. 8, № 3. P. 211–217.

80. Avilés A., Neri N., Nambo M.J. Hematological malignancies and pregnancy: Treat or no treat during first trimester // Int J Cancer. 2012. Vol. 131, № 11. P. 2678–2683.

81. Cheson B.D. et al. Revised response criteria for malignant lymphoma // Journal of Clinical Oncology. 2007. Vol. 25, № 5. P. 579–586.

82. Baryakh EA, et al. Burkitt leukemia/lymphoma: clinical features, diagnostic criteria, therapeutic tactics. Clinical Oncohematology. Fundamental Research and Clinical Practice. 2010;3(2):138–143.

83. Baryakh EA, Myakova NV, Poddubnaya IV. Prevention and treatment of tumor lysis syndrome. In: Poddubnaya IV, Savchenko VG, eds. Russian Clinical Guidelines for the Diagnosis and Treatment of Malignant Lymphoproliferative Disorders. 2018:251–253.

84. Narum S., Westergren T., Klemp M. Corticosteroids and risk of gastrointestinal bleeding: A systematic review and meta-analysis // BMJ Open. 2014. Vol. 4, № 5. P. e004587.

85. Burget D.W., Chiverton S.G., Hunt R.H. Is there an optimal degree of acid suppression for healing of duodenal ulcers? A model of the relationship between ulcer healing and acid suppression // Gastroenterology. Gastroenterology, 1990. Vol. 99, № 2. P. 345–351.

86. Ivashkin VT, et al. Diagnosis and treatment of peptic ulcer disease in adults (Clinical guidelines of the Russian Gastroenterological Association, Russian Society of Colorectal Surgeons, and Russian Endoscopic Society). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2020;30(1):49–70.

87. Scally B. et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials // Lancet Gastroenterol Hepatol. Elsevier Ltd, 2018. Vol. 3, № 4. P. 231–241.

88. Vladimirova LYu, et al. Practical guidelines for the prevention and treatment of nausea and vomiting in cancer patients. Malignant Tumours: RUSSCO Practical Guidelines. 2022;12(3S2):26–39.

89. Navari R.M., Gray S.E., Kerr A.C. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial // J Support Oncol. J Support Oncol, 2011. Vol. 9, № 5. P. 188–195.

90. Navari R.M., Aapro M. Antiemetic Prophylaxis for Chemotherapy-Induced Nausea and Vomiting // New England Journal of Medicine. New England Journal of Medicine (NEJM/MMS), 2016. Vol. 374, № 14. P. 1356–1367.

91. Roy V. et al. Hematopoietic Growth Factors. NCCN Guidelines. Ver 1.2022. 2022.

92. Spirin M., Galstyan G., Drokov M. Central venous access in lymphoma patients (pts) with superior vena cava syndrome (SVCS) // Intensive Care Medicine E[perimental. 2019. Vol. 7, № Suppl. 3:001341. P. 388–389.

93. Konstantinova T.S., Klyasova G.A., Kaplanov K.D. Treatment and prevention of infectious complications in patients with lymphoproliferative disorders. // Russian Clinical Guidelines for the Diagnosis and Treatment of Malignant Lymphoproliferative Disorders; ed. by I.V. Poddubnaya, V.G. Savchenko. 2018. P. 289–311.

94. Srivastava S., Wood P. Secondary antibody deficiency-causes and approach to diagnosis // Clinical Medicine, Journal of the Royal College of Physicians of London. 2016.

95. Somonova O.V. et al. Practical guidelines for the prevention and treatment of thromboembolic complications in cancer patients // Malignant Tumors: RUSSCO Practical Guidelines. 2021. Vol. 11, № 3S2. P. 47.

96. Lyman G.H. et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer // Blood Adv. Blood Adv, 2021. Vol. 5, № 4. P. 927–974.

97. Semiglazova T.Yu. et al. Practical guidelines for the treatment and prevention of mucositis // Malignant Tumors: RUSSCO Practical Guidelines. 2021. Vol. 11, № 3s2. P. 51.

98. Peterson D.E., Bensadoun R.J., Roila F. Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines // Ann Oncol. Ann Oncol, 2011. Vol. 22 Suppl 6, № Suppl 6.

99. Sytov A.V. et al. Practical guidelines for nutritional support in cancer patients // RUSSCO. 2017. P. 524–532.

100. de van der Schueren M.A.E. et al. Systematic review and meta-analysis of the evidence for oral nutritional intervention on nutritional and clinical outcomes during chemo(radio)therapy: current evidence and guidance for design of future trials // Ann Oncol. Ann Oncol, 2018. Vol. 29, № 5. P. 1141–1153.

101. Oktay K. et al. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update // J Clin Oncol. J Clin Oncol, 2018. Vol. 36, № 19. P. 1994–2001.

102. Meirow D., Nugent D. The effects of radiotherapy and chemotherapy on female reproduction // Hum Reprod Update. 2001. Vol. 7, № 6. P. 535–543.

103. Abuzarova G.R. et al. Pain management in adults and children receiving medical care. Methodological guidelines. Pirogov Russian National Research Medical University of the Russian Ministry of Health, 2016. 94 p.

104. Abuzarova G.R. Management of pain syndrome in cancer patients // Russian Clinical Guidelines for the Diagnosis and Treatment of Malignant Lymphoproliferative Disorders; ed. by I.V. Poddubnaya, V.G. Savchenko. 2018. P. 278–288.

105. Paul K.L. Rehabilitation and exercise considerations in hematologic malignancies. // Am J Phys Med Rehabil. 2011. Vol. 90, № 5 Suppl 1. P. S88-94.

106. Cheson B.D. et al. Recommendations for initial evaluation, staging, and response assessment of hodgkin and non-hodgkin lymphoma: The lugano classification // Journal of Clinical Oncology. American Society of Clinical Oncology, 2014. Vol. 32, № 27. P. 3059–3067.

107. Hoorn E.J. Intravenous fluids: balancing solutions // Journal of Nephrology. Springer New York LLC, 2017. Vol. 30, № 4. P. 485–492.

108. Blokhin N.N., Perevodchikova N.I. Chemotherapy of tumor diseases. USSR Academy of Medical Sciences. - M.: Meditsina, 1984.

109. Santarsieri A. et al. Real World Escalated Beacopdac Delivers Similar Outcomes to Escalated Beacopp and Superior Outcomes to Response-Adapted (RATHL) ABVD, While Potentially Reducing Toxicity Compared with Escalated Beacopp // Blood (ASH Annual Meeting Abstracts). 2021. Vol. 138, № Supplement 1. P. 877.

110. Engert A. et al. Pegfilgrastim support for full delivery of BEACOPP-14 chemotherapy for patients with high-risk Hodgkin’s lymphoma: results of a phase II study // Haematologica. 2006. Vol. 91, № 4. P. 546–549.

111. Hancock B.W. et al. ChIVPP alternating with PABIOE is superior to PABIOE alone in the initial treatment of advanced hodgkin’s disease: Results of a british national lymphoma investigation/central lymphoma group randomized controlled trial // Br J Cancer. 2001. Vol. 84, № 10. P. 1293–1300.

112. Pavlovsky S. et al. Randomized trial of CVPP for three versus six cycles in favorable- prognosis and CVPP versus AOPE plus radiotherapy in intermediate-prognosis untreated Hodgkin’s disease // Journal of Clinical Oncology. American Society of Clinical Oncology, 1997. Vol. 15, № 7. P. 2652–2658.

113. Sieber M. et al. Treatment of advanced Hodgkin’s disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin’s Lymphoma Study Group HD6 trial. // Ann Oncol. 2004. Vol. 15, № 2. P. 276–282.

114. Zallio F. et al. Reduced intensity VEPEMB regimen compared with standard ABVD in elderly Hodgkin lymphoma patients: results from a randomized trial on behalf of the Fondazione Italiana Linfomi (FIL) // Br J Haematol. Blackwell Publishing Ltd, 2016. Vol. 172, № 6. P. 879–888.

115. Levis A. et al. Results of a low aggressivity chemotherapy regimen (CVP/CEB) in elderly Hodgkin’s disease patients. // Haematologica. Vol. 81, № 5. P. 450–456.

116. Santoro A. et al. Ifosfamide, gemcitabine, and vinorelbine: A new induction regimen for refractory and relapsed Hodgkin’s lymphoma // Haematologica. 2007. Vol. 92, № 1. P. 35–41.

117. Jeon S.Y. et al. The effect of the dexamethasone, cytarabine, and cisplatin (Dhap) regimen on stem cell mobilization and transplant outcomes of patients with non-hodgkin’s lymphoma who are candidates for up-front autologous stem cell transplantation // Korean Journal of Internal Medicine. Korean Association of Internal Medicine, 2018. Vol. 33, № 6. P. 1169–1181.

118. Ramzi M., Rezvani A., Dehghani M. GDP versus ESHAP Regimen in Relapsed and/or Refractory Hodgkin lymphoma: A Comparison Study. // Int J Hematol Oncol Stem Cell Res. Tehran University of Medical Sciences, 2015. Vol. 9, № 1. P. 10–14.

119. Hu B. et al. Phase-I and randomized phase-II trial of panobinostat in combination with ICE (Ifosfamide, carboplatin, etoposide) in relapsed or refractory classical hodgkin lymphoma // Leuk Lymphoma. Taylor and Francis Ltd, 2018. Vol. 59, № 4. P. 863–870.

120. Gutierrez A. et al. Gemcitabine and oxaliplatinum: An effective regimen in patients with refractory and relapsing Hodgkin lymphoma // Onco Targets Ther. Dove Medical Press Ltd., 2014. Vol. 7. P. 2093–2100.

121. Schellong G. et al. Salvage therapy of progressive and recurrent Hodgkin’s disease: Results from a multicenter study of the pediatric DAL/GPOH-HD Study Group // Journal of Clinical Oncology. 2005. Vol. 23, № 25. P. 6181–6189.

122. Santoro A. et al. Bendamustine in Combination With Gemcitabine and Vinorelbine Is an Effective Regimen As Induction Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma: Final Results of a Multicenter Phase II Study // J Clin Oncol. J Clin Oncol, 2016. Vol. 34, № 27. P. 3293–3299.

123. O’Connor O.A. et al. Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin’s lymphoma: an international, multicentre, single-arm, phase 1-2 trial // Lancet Oncol. Lancet Oncol, 2018. Vol. 19, № 2. P. 257–266.

124. Kersten M.J. et al. Combining brentuximab vedotin with dexamethasone, high-dose cytarabine and cisplatin as salvage treatment in relapsed or refractory Hodgkin lymphoma: the phase II HOVON/LLPC Transplant BRaVE study // Haematologica. Haematologica, 2021. Vol. 106, № 4.

125. Lynch R.C. et al. Dose-dense brentuximab vedotin plus ifosfamide, carboplatin, and etoposide for second-line treatment of relapsed or refractory classical Hodgkin lymphoma: a single centre, phase 1/2 study // Lancet Haematol. Lancet Haematol, 2021. Vol. 8, № 8. P. e562–e571.

126. Garcia-Sanz R. et al. Brentuximab vedotin and ESHAP is highly effective as second-line therapy for Hodgkin lymphoma patients (long-term results of a trial by the Spanish GELTAMO Group) // Ann Oncol. Ann Oncol, 2019. Vol. 30, № 4. P. 612–620.

127. Long G. V. et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer // Annals of Oncology. Oxford University Press, 2018. Vol. 29, № 11. P. 2208–2213.

128. Herrera A.F. et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma // Blood. Blood, 2018. Vol. 131, № 11. P. 1183–1194.

129. Advani R.H. et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results // Blood. Blood, 2021. Vol. 138, № 6. P. 427–438.

130. Caballero M.D. et al. BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors // Bone Marrow Transplant. Bone Marrow Transplant, 1997. Vol. 20, № 6.

131. Colita A. et al. LEAM vs. BEAM vs. CLV Conditioning Regimen for Autologous Stem Cell Transplantation in Malignant Lymphomas. Retrospective Comparison of Toxicity and Efficacy on 222 Patients in the First 100 Days After Transplant, On Behalf of the Romanian Society for Bon // Front Oncol. Front Oncol, 2019. Vol. 9. P. 892.

132. Sharma A. et al. Comparison of BEAM vs. LEAM regimen in autologous transplant for lymphoma at AIIMS. // Springerplus. Springerplus, 2013. Vol. 2. P. 489.

133. Visani G. et al. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. // Blood. 2011. Vol. 118, № 12. P. 3419–3425.

134. Visani G. et al. XRCC1 399GG genotype predicts significantly longer overall survival in resistant lymphoma patients treated with Benda-EAM and ASCT // Bone Marrow Transplant. Nature Publishing Group, 2020. Vol. 55, № 4. P. 818–820.

135. Sarzhevsky V.O., Samoylova A.A., Melnichenko V.Ya. Safety and efficacy of the BeEAC regimen as conditioning prior to autologous hematopoietic stem cell transplantation in relapsed and refractory lymphomas // Clinical Oncohematology. Basic Research and Clinical Practice. 2020. Vol. 13, № 2. P. 185–192.

136. Bubalo J. et al. Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee // Biol Blood Marrow Transplant. Biol Blood Marrow Transplant, 2014. Vol. 20, № 5. P. 600–616.

137. Jagannath S. et al. Prognostic factors for response and survival after high-dose cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation for relapsed Hodgkin’s disease // J Clin Oncol. J Clin Oncol, 1989. Vol. 7, № 2. P. 179–185.

138. Krause D.S. et al. CD34: Structure, biology, and clinical utility // Blood. American Society of Hematology, 1996. Vol. 87, № 1. P. 1–13.

139. Giralt S. et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: Consensus guidelines and recommendations // Biology of Blood and Marrow Transplantation. Elsevier, 2014. Vol. 20, № 3. P. 295–308.

140. Stiff P.J. et al. Transplanted CD34 + Cell Dose Is Associated with Long-Term Platelet Count Recovery following Autologous Peripheral Blood Stem Cell Transplant in Patients with Non-Hodgkin Lymphoma or Multiple Myeloma // Biology of Blood and Marrow Transplantation. Biol Blood Marrow Transplant, 2011. Vol. 17, № 8. P. 1146–1153.

141. Passos-Coelho J.L. et al. Predictive factors for peripheral-blood progenitor-cell collections using a single large-volume leukapheresis after cyclophosphamide and granulocyte- macrophage colony-stimulating factor mobilization // Journal of Clinical Oncology. American Society of Clinical Oncology, 1995. Vol. 13, № 3. P. 705–714.

142. Hohaus S. et al. Successful autografting following myeloablative conditioning therapy with blood stem cells mobilized by chemotherapy plus rhG-CSF. // Exp Hematol. 1993. Vol. 21, № 4. P. 508–514.

143. Olivieri A. et al. Proposed definition of “poor mobilizer” in lymphoma and multiple myeloma: An analytic hierarchy process by ad hoc working group Gruppo ItalianoTrapianto di Midollo Osseo // Bone Marrow Transplant. Bone Marrow Transplant, 2012. Vol. 47, № 3. P. 342–351.

144. Wood W.A. et al. Effectiveness of Etoposide Chemomobilization in Lymphoma Patients Undergoing Autologous Stem Cell Transplantation // Bone Marrow Transplant. NIH Public Access, 2013. Vol. 48, № 6. P. 771.

145. Afanasyeva O.I., Voinov V.A., Goldfarb Yu.S. Extracorporeal hemocorrection: terminology, linguistic equivalents. St. Petersburg, 2016. P. 7–15.

146. Ikeda K. et al. Adverse Events Associated With Infusion of Hematopoietic Stem Cell Products: A Prospective and Multicenter Surveillance Study // Transfusion Medicine Reviews. W.B. Saunders, 2018. Vol. 32, № 3. P. 186–194.

147. Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group // Am J Clin Oncol. 1982. Vol. 5, № 6. P. 649–655.

148. Meignan M., Gallamini A., Haioun C. Report on the First International Workshop on interim-PET scan in lymphoma // Leukemia and Lymphoma. 2009. Vol. 50, № 8. P. 1257–1260.

149. Sarzhevsky V.O., Mamedova A.A., Mochkin N.E. et al. Combination of Nivo-DHAP followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with relapsed and refractory classical Hodgkin lymphoma: results of a multicenter prospective clinical trial (ClinicalTrials.gov, NCT04091490) // Clinical Oncohematology. Basic Research and Clinical Practice. 2024. Vol. 17, № 1. P. 1–10.

150. Mangasarova Ya.K., Moiseeva T.N., Margolin O.V. et al. Nivo-BeGEV as conditioning for autologous hematopoietic stem cell transplantation in relapsed and refractory classical Hodgkin lymphoma: results of a multicenter prospective clinical trial // Clinical Oncohematology. Basic Research and Clinical Practice. 2023. Vol. 16, № 3. P. 280–6.

151. Mei MG, Lee HJ, Palmer JM, et al. Response-adapted anti-PD-1–based salvage therapy for Hodgkin lymphoma with nivolumab alone or in combination with ICE. Blood. 2022;139(25):3605–16.

152. Cheson B. D. et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification // Journal of Clinical Oncology. – 2014. – Vol. 32. – № 27. – P. 3059-3067.

153. Troitskaya V.V., Parovichnikova E.N., Galstyan G.M. et al. Hyperleukocytosis, prevention and treatment of tumor lysis syndrome in patients with hematological diseases // Supportive Care in the Treatment of Blood System Diseases. Practical Guide / ed. by E.N. Parovichnikova, G.M. Galstyan. Moscow: Praktika, 2024. P. 35-57.

154. Protocols of Clinical Guidelines for Supportive Care in Oncology. 4th edition, revised and expanded. Edited by Academician of the Russian Academy of Sciences M.I. Davydov. 2020.

155. Cooper K.L. et al. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: Systematic review and meta-analysis // BMC Cancer. BioMed Central, 2011. Vol. 11, № 1. P. 1–11.

156. Aapro M.S. et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours // Eur. J. Cancer. Elsevier, 2011. Vol. 47, № 1. P. 8–32

157. Perevodchikova N.I., Gorbunova V.A. Guide to chemotherapy of tumor diseases // Moscow: Practical Medicine. – 2015.

158. Salim O. et al. Retrospective analysis of toxicity profiles of two platinum-based salvage regimens in relapsed/refractory lymphoma: DHAP versus ESHAP // UHOD-ULUSLARARASI HEMATOLOJI-ONKOLOJI DERGISI. – 2016. – Vol. 26. – № 1.

159. Lambertini M., F. A. Peccatori, I. Demeestere, et al. Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol (2020)

160. Korsantiya M.N. et al. Experience with brentuximab vedotin in the treatment of children and young adults with primary refractory and relapsed Hodgkin lymphoma // Pediatric Hematology/Oncology and Immunopathology. – 2020. – Vol. 19. – № 1. – P. 47-52.

161. Wilson M. R. et al. Frontline management of nodular lymphocyte predominant Hodgkin lymphoma-a retrospective UK multicentre study //British journal of haematology. – 2019.

162. Eichenauer DA, Fuchs M. Treatment of Nodular Lymphocyte-Predominant Hodgkin Lymphoma: Where Do We Stand? Where Do We Go? Cancers (Basel). 2023 Jun 23;15(13):3310.

163. Sandra Purz, Christine Mauz-Ko¨rholz, Dieter Ko¨rholz, et al. [18F] Fluorodeoxyglucose positron emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin’s Lymphoma. Journal of Clinical Oncology, volume 29, number 26, 3523 – 3528 (2011

164. Aamna Hassan, Maimoona Siddique, Humayun Bashir, et al. [18F]-FDG PET-CT imaging versus bone marrow biopsy in pediatric Hodgkin’s lymphoma: a quantitative assessment of marrow uptake and novel insights into clinical implications of marrow involvement. Eur J Nucl Med Mol Imaging (2017) 44:1198–1206

165. Christopher J. Forlenza, Jaclyn Rosenzweig, et al. Brentuximab vedotin after autologous transplantation in pediatric patients with relapsed/refractory Hodgkin lymphoma. Blood Adv (2023) 7 (13): 3225–3231.

166. Sara Ebrahimi, Adrina Habibzadeh, Soroush Khojasteh-Kaffash et al., Immune checkpoint inhibitors therapy as the game-changing approach for pediatric lymphoma: A brief landscape. Critical Reviews in Oncology/Hematology, volume 193 (2024), 104225

167. Christopher L Tinkle, Noelle L Williams, Huiyun Wu, et al. Treatment patterns and disease outcomes for pediatric patients with refractory or recurrent Hodgkin lymphoma treated with curative-intent salvage radiotherapy. Radiother Oncol. 2019 Feb 5;134:89–95

168. C Mauz-Körholz, T Lange, D Hasenclever, B Burkhardt, A C Feller, W Dörffel et al. Pediatric Nodular Lymphocyte-predominant Hodgkin Lymphoma: Treatment Recommendations of the GPOH-HD Study Group. Klin Padiatr. (2015); 227(6-7):314-21.

169. Dennis A. Eichenauer, Andreas Engert. How I treat nodular lymphocyte-predominant Hodgkin lymphoma. Blood (2020) 136 (26): 2987–2993.

170. David C. Hodgson MD, Karin Dieckmann MD, Stephanie Terezakis, Louis Constine. Implementation of contemporary radiation therapy planning concepts for pediatric Hodgkin lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group. Practical Radiation Oncology, volume 5, issue 2 (2015), pages 85-92

171. Marr K, Ronsley R, Nadel H, Douglas K, Gershony S, Strahlendorf C, Davis JH, Deyell RJ. Ifosfamide, gemcitabine, and vinorelbine is an effective salvage regimen with excellent stem cell mobilization in relapsed or refractory pediatric Hodgkin lymphoma. Pediatr Blood Cancer. 2020 Apr;67(4):e28167. doi: 10.1002/pbc.28167. Epub 2020 Jan 11.

172. Algeri M, Locatelli F. Pembrolizumab (and friends) in pediatric malignancies: should we consider Hodgkin lymphoma a world of its own? Ann Transl Med. 2020 Sep;8(17):1112. doi: 10.21037/atm.2020.04.54.

173. Galstyan G.M. Infusion therapy in patients with hematological diseases // Supportive Care in the Treatment of Blood System Diseases. Edited by E.N. Parovichnikova, G.M. Galstyan. 2024. P. 495–501.

174. Kamelskikh D.V. et al. Transfusions of donor blood and (or) its components in adult patients with hematological diseases. // Supportive Care in the Treatment of Blood System Diseases. Edited by E.N. Parovichnikova, G.M. Galstyan. Praktika Publishing House. 2024. P. 387–407.

175. Galstyan G.M., Spirin M.V. Vascular access in hematology // Praktika Publishing House. 2021. P. 232.

176. Vorobyov A.I. et al. Critical conditions in hemoblastoses (typical forms and survival in the intensive care unit setting). // Therapeutic Archive. 1993. Vol. 65, № 7. P. 3–6.

177. Galstyan G.M., Gorodetsky V.M. Experience of the intensive care unit of the National Research Center for Hematology of the Ministry of Health and Social Development of the Russian Federation // Clinical Oncohematology. 2011. Vol. 4, № 1. P. 75–78.

178. Vuolio T., Kuittinen O., Väyrynen J.P., Teppo H., Prusila R.E.I., Rämet M., Kuitunen H., Paloneva T., Kuusisto M.E.L. R-bendamustine in the Treatment of Nodular Lymphocyte Predominant Hodgkin Lymphoma—An Extended Follow-up. Br. J. Haematol. 2023 doi: 10.1111/bjh.18896

179. Gotti M., Sciarra R., Pulsoni A., Merli F., Luminari S., Zerbi C., Trentin L., Re A., Rusconi C., Viviani S., et al. Role of Rituximab Addition to First-Line Chemotherapy Regimens in Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi. HemaSphere. 2023;7:e837. doi: 10.1097/HS9.0000000000000837.

180. Pusic I, Jiang SY, Landua S, Uy GL, Rettig MP, Cashen AF, Westervelt P, Vij R, Abboud CN, Stockerl-Goldstein KE, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14:1045–1056. doi: 10.1016/j.bbmt.2008.07.004

181. Gertz, M., Wolf, R., Micallef, I. et al. Clinical impact and resource utilization after stem cell mobilization failure in patients with multiple myeloma and lymphoma. Bone Marrow Transplant 45, 1396–1403 (2010) .doi.org/10.1038/bmt.2009.370

182. Zheng G, He J, Cai Z, He D, Luo Y, Shi J, Wei G, Sun J, Zheng W. A retrospective study of autologous stem cell mobilization by G-CSF in combination with chemotherapy in patients with multiple myeloma and lymphoma. Oncol Lett. 2020 Jan;19(1):1051-1059. doi: 10.3892/ol.2019.11177

183. «Lymphocyte-Predominant Hodgkin's Disease in Children: A Case Study and Review of the Literature». James R Stier, Robert J Vasquez. Case Rep Oncol Med. 2015 Mar 24; 2015: 351431. doi:10.1155/2015/351431

184. «Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents – a comprehensive review of biology, clinical course and treatment options». Ananth Shankar and Stephen Daw. British Journal of Haematology, 2012. doi:10.1111/bjh.12055

185. "Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin's lymphoma". Santoro A., Magagnoli M., Spinа M et al. 2007. Haematologica 92(1):35-41.

186. «Lymphocyte-predominant Hodgkin lymphoma: what is the optimal treatment?» Michelle Fanale. Hematology Am Soc Hematol Educ Program 2013 (1): 406–413.

187. «Treatment of children and adolescents with early stage nodular lymphocyte predominant Hodgkin lymphoma with a low intensity short duration chemotherapy regimen (CVP)–on behalf of the EuroNet-PHL Group». Shankar et al. Blood, 2006, vol. 108 11pg. 2471

188. Optimizing Stem Cells Mobilization Strategies to Ameliorate Patient Outcomes: A Review of Guide- lines and Recommendations. Saeed Mohammadi, Ashraf Malek Mohammadi, Mohsen Nikbakht, Amir Hossein Norooznezhad, Kamran Alimoghaddam, Ardeshir Ghavamzadeh. Int J Hematol Oncol Stem Cell Res. 2017 Jan 1;11(1):78–88.

189.«Stem cell mobilization and collection from pediatric patients and healthy children» Musa Karakukcu, Ekrem Unal. Transfusion and Apheresis Science, Volume 53, Issue 1, August 2015, Pages 17-22

190.«Successful mobilization of peripheral blood stem cells in children with cancer using plerixafor (Mozobil) and granulocyte-colony stimulating factor» Boryana Avramova, Maya Yordanova, Dobrin Konstantinov, Dragan Bobev. Drug Des Devel Ther. 2011:5:407-9. Epub 2011 Aug 26.

191. Unal A, Sari I, Deniz K, Ozkan M, Kontas O, Eser B, Cetin M. Familial nodular lymphocyte predominant Hodgkin lymphoma: Successful treatment with CHOP plus rituximab. Leuk Lymphoma. 2005 Nov;46(11):1613-7. doi: 10.1080/10428190500236502. PMID: 16236615

Appendix A1. Working Group Composition

Elena A. Demina — MD, PhD, Professor, Department of Hematology and Cellular Therapy, Institute for Advanced Training of Doctors, National Medical and Surgical Center named after N.I. Pirogov of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematology.
Gayane S. Tumyan — MD, PhD, Professor, Department of Oncology and Palliative Medicine, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Leading Researcher, Department of Chemotherapy of Hemoblastoses, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematology.
Tatyana N. Moiseeva — Candidate of Medical Sciences, Head of the Consultative Hematological Department with a Day Hospital for Intensive High-Dose Chemotherapy, Member of the Association for the Promotion of the Development of Hematology, Transfusiology, and Bone Marrow Transplantation "National Hematology Society"
Natalia B. Mikhailova — MD, PhD, Head of the Department of Clinical Oncology (Chemotherapy), R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Member of the Russian Society of Oncohematology.
Dmitry V. Motorin — Candidate of Medical Sciences, Hematologist, Department of Chemotherapy of Oncohematological Diseases and Bone Marrow Transplantation No. 2, Almazov National Medical Research Center of the Russian Ministry of Health
Natalia V. Myakova — MD, PhD, Professor, Deputy Chief Medical Officer for Medical Work, Head of the Oncohematology Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Member of the National Society of Pediatric Hematologists and Oncologists
Alexander G. Rumyantsev — Academician of the Russian Academy of Sciences, MD, PhD, Professor, General Director of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, President of the National Society of Pediatric Hematologists and Oncologists
Alexey A. Maschan — Corresponding Member of the Russian Academy of Sciences, MD, PhD, Professor, Deputy General Director of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Board Member of the National Society of Pediatric Hematologists and Oncologists
Kamil D. Kaplanov — MD, PhD, Head of Hematology Department No. 11, S.P. Botkin City Clinical Hospital of the Moscow Healthcare Department, Member of the Russian Society of Oncohematology and the Association for the Promotion of the Development of Hematology, Transfusiology, and Bone Marrow Transplantation "National Hematology Society"
Vladislav O. Sarzhevsky — MD, PhD, Deputy Chief Medical Officer for Oncology, National Medical and Surgical Center named after N.I. Pirogov of the Russian Ministry of Health
Roman G. Shmakov — MD, PhD, Professor of the Russian Academy of Sciences, Highest Qualification Category Physician, Director of the Academician V.I. Krasnopolsky Moscow Regional Research Institute of Obstetrics and Gynecology, Board Member of the Russian Society of Obstetricians and Gynecologists
Natalia A. Falaleeva — MD, PhD, Head of the Department of Antitumor Drug Therapy, A.F. Tsyb Medical Radiological Research Center — branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Member of the Association of Oncologists of Russia and the Russian Association of Therapeutic Radiation Oncologists.
Vadim V. Ptushkin — MD, PhD, Professor, Deputy Chief Medical Officer for Hematology, S.P. Botkin City Clinical Hospital, Chief freelance specialist hematologist of the Moscow Healthcare Department, Member of the Association for the Promotion of the Development of Hematology, Transfusiology, and Bone Marrow Transplantation "National Hematology Society" and the Russian Society of Oncohematology.
Evgeny A. Osmanov — MD, PhD, Professor, Head of the Department of Hematology and Bone Marrow Transplantation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor of the Department of Oncology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Board Member of the Russian Society of Oncohematology.
Irina V. Poddubnaya — Academician of the Russian Academy of Sciences, Honored Worker of Education of the Russian Federation, D.Sc. (Medicine), Professor, Head of the Department of Oncology and Palliative Medicine, Vice-Rector for Clinical Work and International Cooperation at the Russian Medical Academy of Continuous Professional Education (RMANPO) of the Russian Ministry of Health, Chairman of the Russian Society of Oncohematology.
Vadim V. Baykov — D.Sc. (Medicine), Professor at the Department of Pathological Anatomy, Head of the Pathomorphology Laboratory at the Research Institute of Pediatric Oncology, Hematology and Transplantology named after R.M. Gorbacheva, First Pavlov Saint Petersburg State Medical University of the Russian Ministry of Health, Member of the Presidium of the Russian Society of Pathologists, Member of the Board of the Russian Society of Oncohematology.
Alla M. Kovrigina — D.Sc. (Biology), Professor at the Department of Pathological Anatomy, Cytology and Molecular Pathology at the Advanced Training Institute of the Federal Medical-Biological Agency (FMBA) of Russia, Head of the Department of Pathological Anatomy at the National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Presidium of the Russian Society of Pathologists, Member of the Board of the Russian Society of Oncohematology.
Dmitry M. Konovalov — Ph.D. (Medicine), Head of the Pathological Anatomy Department at the National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev of the Russian Ministry of Health
Olga V. Mukhortova — D.Sc. (Medicine), Professor at the Department of Radiology, Leading Researcher at the Department of Nuclear Diagnostics, National Medical Research Center for Cardiovascular Surgery named after A.N. Bakulev of the Russian Ministry of Health
Oksana P. Trofimova — D.Sc. (Medicine), Leading Researcher at the Radiology Department, National Medical Research Center for Oncology named after N.N. Blokhin of the Russian Ministry of Health, Associate Professor at the Department of Oncology, Russian Medical Academy of Continuous Professional Education (RMANPO) of the Russian Ministry of Health, Member of the Russian Association of Therapeutic Radiation Oncologists.
Vladimir M. Sotnikov — D.Sc. (Medicine), Head of the Radiation Therapy Laboratory, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health.
Nikolay V. Ilyin — D.Sc. (Medicine), Professor, Professor at the Department of Radiology, Surgery and Oncology, Chief Researcher at the Department of Radiation and Combined Treatment Methods, Russian Scientific Center for Radiology and Surgical Technologies named after Academician A.M. Granov of the Russian Ministry of Health.
Yulia N. Vinogradova — D.Sc. (Medicine), Head of the Department of Radiation and Combined Treatment Methods, Chief Researcher at the Department of Radiation and Combined Treatment Methods, Russian Scientific Center for Radiology and Surgical Technologies named after Academician A.M. Granov of the Russian Ministry of Health.
Alexey V. Nechesnyuk — D.Sc. (Medicine), Head of the Radiation Therapy Department, National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after D. Rogachev, Member of the National Society of Pediatric Hematologists and Oncologists
Roman A. Parkhomenko — D.Sc. (Medicine), Senior Researcher at the Laboratory of Complex Treatment Methods for Childhood Cancers, Russian Scientific Center of Roentgenology and Radiology of the Russian Ministry of Health

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists.

2. Oncologists.

3. Pediatric oncologists/hematologists.

4. Radiation therapists, radiologists, radiodiagnosticians.

5. Medical students.

Methodology for evidence collection

Methods used for the collection/selection of evidence:

search for publications in peer-reviewed journals with an impact factor >0.3;
electronic database searching.

Databases used to gather/select evidence. The evidence base for the recommendations consists of publications included in the Cochrane Library, PubMed, and MEDLINE databases.

Methods used for evidence analysis:

reviews of published meta-analyses;

systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

· expert consensus;

· evaluation of the significance of evidence in accordance with the evidence rating scheme (Tables A2.1, A2.2, A2.3).

In these clinical guidelines, the levels of evidence for recommendations are given in parentheses in accordance with the scales developed by the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO).

Table A2.1. Scale for grading the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

LoE	Definition
1	Systematic reviews of studies with reference standard control or systematic reviews of randomized clinical trials with meta-analysis.
2	Individual studies with reference method control or individual randomized clinical trials and systematic reviews of studies of any design, excluding randomized clinical trials with meta-analysis
3	Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies.
4	Non-comparative studies, case reports.
5	Only mechanism of action rationale or expert opinion is available.

Table A2.2. Scale for assessing the levels of certainty of evidence for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Level of evidence	Definition
1	Systematic review of RCTs with meta-analysis.
2	Individual RCTs and systematic reviews of studies of any design, excluding RCTs, with meta-analysis.
3	Non-randomized comparative studies, including cohort studies.
4	Non-comparative studies, case reports or case series, case-control studies.
5	Only rationale of intervention mechanism (preclinical studies) or expert opinion is available.

Table A2.3. Scale for assessing the grades of recommendation for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Grade of Recommendation	Definition
A	Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or moderate methodological quality, and their conclusions on the outcomes of interest are consistent).
B	Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or moderate methodological quality, and/or their conclusions on the outcomes of interest are inconsistent).
C	Weak recommendation (lack of proper quality evidence, all considered efficacy criteria (outcomes) are unimportant, all studies have low methodological quality and their conclusions regarding the outcomes of interest are inconsistent).

Methodology for validation of guidelines

Methods of recommendation validation:

external expert review;
internal expert review.

Description of the guideline validation methodology. The preliminary version of these recommendations was reviewed by independent experts who were asked to comment on the quality of evidence interpretation and the development of the recommendations. An expert assessment of the presentation of the recommendations and their readability was also performed.

The recommendations have been discussed and approved by leading specialists from specialized federal centers of the Russian Federation and practicing physicians. The draft clinical guidelines were reviewed at meetings of the working group in 2022–2024, at the Expert Forum on the Diagnosis and Treatment of Malignant Lymphoproliferative Diseases ("Lymphoforum"), the Annual Russian Conference with International Participation "Malignant Lymphomas", and within the framework of the 4th Congress of Hematologists of Russia.

Final edition. For the final edition and quality control, the recommendations were re-evaluated by the members of the authoring team, who concluded that all essential remarks and comments from experts were taken into account, and the risk of bias during development was minimized.

Appendix A3. Reference Materials

Appendix A3.1. Drug treatment regimens for HL

During chemotherapy, it is recommended to monitor the patient's weight and recalculate the doses of antineoplastic agents if the weight changes.

3.1.1 First-line therapy regimens for classical Hodgkin lymphoma in patients over 18 years of age

ABVD [22, 23, 26]
Drug	Standard dose	Route of administration	Days of administration
Doxorubicin**	25 mg/m²	IV infusion or bolus	1, 15 (every 14 days)
Bleomycin**	10 mg/m²	IV bolus	1, 15 (every 14 days)
Vinblastine**	6 mg/m² (maximum 10 mg)	IV, over 5–10 min	1, 15 (every 14 days)
Dacarbazine**	375 mg/m²	IV infusion	1, 15 (every 14 days)
Treatment is resumed on day 29
BEACOPP-escalated [4, 25, 27]
Drug	Standard dose	Route of administration	Days of administration
Cyclophosphamide**	1250 mg/m²	IV infusion	1
Doxorubicin**	35 mg/m²	IV infusion or bolus	1
Etoposide**	200 mg/m²	IV infusion	1–3
#Procarbazine or #Dacarbazine	100 mg/m² 250 mg/m²	orally IV infusion	1–7 1–2
Bleomycin**	10 mg/m²	IV bolus	8
Vincristine**	1.4 mg/m² (maximum 2 mg)	IV, over 5–10 min	8
Prednisolone**	40 mg/m²	orally	1–14
G-CSF	According to the instructions for medical use		From day 8 to day 12 or until leukocyte recovery
Treatment is resumed on day 22 It is recommended to increase fluid intake to up to 2 liters per day on the eve and from the first day of the cycle. In case of high tumor burden, each patient is prescribed #allopurinol at a dose of 300 mg/day, and hydration therapy of up to 3 L/m²is administered during the first 3 days of the cycle with strict monitoring of diuresis and electrolyte parameters [21, 153] Replacement of #procarbazine with #dacarbazine** 250 mg/m² IV infusion or bolus, days 2–3 is possible [108, 109]
BEACOPP-14 [26, 31]
Drug	Standard dose	Route of administration	Days of administration
Cyclophosphamide**	650 mg/m²	IV infusion	1
#Doxorubicin**	25 mg/m²	IV infusion or bolus	1
#Etoposide**	100 mg/m²	IV infusion	1–3
#Procarbazine or #Dacarbazine	100 mg/m² 375 mg/m²	Oral IV infusion	1–7 1
Bleomycin**	10 mg/m²	IV bolus	8
Vincristine**	1.4 mg/m² (maximum 2 mg)	IV, over 5–10 min	8
Prednisolone**	40 mg/m²	Oral	1–7 discontinuation of prednisolone** in a single day on day 8 of the cycle. If withdrawal syndrome occurs, over 3 days
G-CSF	According to the instructions for medical use		Days 9–13 on a scheduled basis regardless of leukocyte count
Treatment is resumed on day 15 It is recommended to increase fluid intake to up to 2 liters per day on the eve and from the first day of the cycle. In case of high tumor burden, each patient is prescribed #allopurinol at a dose of 300 mg/day, and hydration therapy of up to 3 L/m²is administered during the first 3 days of the cycle with strict monitoring of diuresis and electrolyte parameters [21, 153] Replacement of #procarbazine with #dacarbazine 375 mg/m² IV infusion or bolus, day 1 is possible [108, 109] Long-acting G-CSF formulations may be used in patients older than 18 years to prevent and treat neutropenia induced by cytotoxic tumor chemotherapy: pegfilgrastim 6 mg or empegfilgrastim 7.5 mg subcutaneously, once, on day 4 or 5 of the cycle (24–48 hours after the completion of antineoplastic drug administration) [110, 154, 155, 156]
EACOPP-14 [8]
Drug	Standard dose	Route of administration	Days of administration
Cyclophosphamide**	650 mg/m²	IV infusion	1
Doxorubicin**	50 mg/m²	IV infusion or bolus	1
#Etoposide**	100 mg/m²	IV infusion	1–3
#Procarbazine or #Dacarbazine	100 mg/m² 375 mg/m²	Oral IV infusion	1–7 1
Vincristine**	1.4 mg/m² (maximum 2 mg)	IV, over 5–10 min	8
Prednisolone Or Dexamethasone	40 mg/m² 20 mg	Oral IV	1–7 discontinuation of prednisolone** in a single day on day 8 of the cycle. If withdrawal syndrome occurs, over 3 days 1–3
G-CSF	According to the instructions for medical use		Days 9–13 on a scheduled basis regardless of leukocyte count
Treatment is resumed on day 15 It is recommended to increase fluid intake to up to 2 liters per day on the eve and from the first day of the cycle. In case of high tumor burden, each patient is prescribed #allopurinol at a dose of 300 mg/day, and hydration therapy of up to 3 L/m²is administered during the first 3 days of the cycle with strict monitoring of diuresis and electrolyte parameters [21, 153] Replacement of #procarbazine with #dacarbazine 375 mg/m² IV infusion or bolus, day 1 is possible [108, 109] Long-acting G-CSF formulations may be used in patients older than 18 years to prevent and treat neutropenia induced by cytotoxic tumor chemotherapy: pegfilgrastim 6 mg or empegfilgrastim 7.5 mg subcutaneously, once, on day 4 or 5 of the cycle (24–48 hours after the completion of antineoplastic drug administration) [110, 154, 155, 156]
BV-AVD [39]
Drug	Standard dose	Route of administration	Days of administration
Brentuximab vedotin**	1.2 mg/kg	IV infusion over 30 minutes, 1 hour after the completion of AVD administration	1, 15
Doxorubicin**	25 mg/m²	IV infusion or bolus	1, 15
Vinblastine**	6 mg/m² (maximum 10 mg)	IV, over 5–10 min	1, 15
Dacarbazine**	375 mg/m²	IV infusion	1, 15
Treatment is resumed on day 29 It is recommended to increase fluid intake to up to 2 liters per day on the eve and from the first day of the cycle. In case of high tumor burden, each patient is prescribed #allopurinol** at a dose of 300 mg/day, and hydration therapy of up to 3 L/m²is administered during the first 3 days of the cycle with strict monitoring of diuresis and electrolyte parameters [21, 153]. Primary G-CSF prophylaxis is recommended for all patients regardless of age, starting from the first dose, initiated within the first 4 days after the administration of antineoplastic drugs, but no later than day 5 [39]. For all drugs, if the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

3.1.2 Hodgkin lymphoma therapy regimens in patients aged 3–18 years

OEPA [41]
Drug	Standard dose	Route of administration	Days of administration
Prednisolone**	60 mg/m²/day divided into 3 doses	orally	1–15
Vincristine**	1.5 mg/m² (max. 2 mg)	IV bolus	1, 8, 15
Doxorubicin**	40 mg/m²	IV over 1–6 hours	1, 15
Etoposide**	125 mg/m²	IV over 1–2 hours	2–6
Treatment is resumed on day 29
COPDAC [41]
Drug	Standard dose	Route of administration	Days of administration
Prednisolone**	40 mg/m²/day orally divided into 3 doses	orally	1–15
Vincristine**	1.5 mg/m² (max. 2 mg)	IV bolus	1, 8
#Dacarbazine**	250 mg/m²	IV over 30 min	1, 2, 3
Cyclophosphamide**	500 mg/m²	IV over 1 hour	1, 8
Treatment is resumed on day 29

3.1.3 Treatment regimens for elderly patients with Hodgkin lymphoma

ChlVPP [111]
Drug	Standard dose	Route of administration	Days of administration
Chlorambucil**	6 mg/m²	orally	1–14
Procarbazine**	100 mg/m²	IV	1–14
Vinblastine**	6 mg/m²	IV	1, 8
Prednisolone**	40 mg/m²	orally	1–14
Treatment is resumed on day 29
CVPP [112]
Drug	Standard dose	Route of administration	Days of administration
Cyclophosphamide**	600 mg/m²	IV	1, 8
Procarbazine**	100 mg/m²	Oral	1–14
Vinblastine**	6 mg/m²	IV	1, 8
Prednisolone**	40 mg/m²	orally	1–14
Treatment is resumed on day 29
COPP [113]
Drug	Standard dose	Route of administration	Days of administration
Cyclophosphamide**	650 mg/m²	IV	1, 8
Procarbazine**	100 mg/m²	Oral	1–14
Vincristine	1.4 mg/m² (maximum 2 mg)	IV, over 5–10 min	1, 8
Prednisolone**	40 mg/m²	orally	1–14
Treatment is resumed on day 29
IVDG [48]
Drug	Standard dose	Route of administration	Days of administration
#Idarubicin**	5 mg/m²	IV	1, 15
Vinblastine**	5 mg/m²	IV	1, 15
Dacarbazine**	375 mg/m²	IV	1, 15
#Gemcitabine**	800 mg/m²	IV	1, 15
Treatment is resumed on day 29 Reduction of the #gemcitabine dose to 500 mg/m² and dacarbazine to 300 mg/m² is provided if the leukocyte count is <2×10⁹/L and/or platelet count is <75×10⁹/L by the day of the next drug administration, i.e., by the end of the break, or in case of grade IV leukopenia according to WHO criteria lasting >4 days during the previous cycle.
VEPEMB [114]
Drug	Standard dose	Route of administration	Days of administration
Vinblastine**	6 mg/m²	IV	1
Cyclophosphamide**	500 mg/m²	IV	1
#Procarbazine**	100 mg/m²	orally	1–5
Prednisolone**	30 mg/m²	orally	1–5
Etoposide**	60 mg/m²	orally	15–19
#Mitoxantrone**	6 mg/m²	IV	15
#Bleomycin**	10 mg/m²	IV	15
Treatment is resumed on day 29
CVP [4]
Drug	Standard dose	Route of administration	Days of administration
Cyclophosphamide**	1000 mg/m²	IV	1
Vinblastine**	6 mg/m²	IV	1
Prednisolone**	40 mg/m²	orally	1–5
Treatment is resumed on day 22

3.1.4 Second-line and subsequent therapy regimens for Hodgkin lymphoma

IGEV for patients over 18 years of age [116, 171, 185]

Drug	Standard dose	Route of administration	Days of administration
Prednisolone**	100 mg	orally	1–4
Ifosfamide**	2000 mg/m²	IV infusion	1–4
#Vinorelbine**	20 mg/m²	IV	1
#Gemcitabine**	800 mg/m²	IV infusion	1, 4

IGEV for patients under 18 years of age [116, 171]

Drug	Standard dose	Route of administration
Methylprednisolone**	100 mg	IV drip
Ifosfamide**	2000 mg/m²	IV infusion
#Vinorelbine**	25 mg/m²	IV
#Gemcitabine**	800 mg/m²	IV infusion

DHAP for patients over 18 years of age [158]

Drug	Standard dose	Route of administration	Days of administration
Dexamethasone**	40 mg	IV	1–4
#Cisplatin**	100 mg/m²	IV drip, 24-hour infusion	1
#Cytarabine**	2 g/m²	IV drip twice daily	2

ESHAP for patients over 18 years of age [158]

Drug	Standard dose	Route of administration	Days of administration
#Etoposide**	40 mg/m²	IV infusion	1–4
Methylprednisolone**	500 mg	IV drip	1–4
#Cisplatin**	25 mg/m²/day	Continuous IV infusion	1–4
#Cytarabine**	2000 mg/m²	IV drip,	5

ICE for patients over 18 years of age [119]

Drug	Standard dose	Route of administration	Days of administration
#Etoposide**	100 mg/m²	IV drip	1–3
Ifosfamide**	5000 mg/m²	IV 24-hour infusion	1
#Carboplatin**	AUC 5	IV infusion	1

GDP for patients over 18 years of age [118]

Drug	Standard dose	Route of administration	Days of administration
#Cisplatin**	75 mg/m²	IV drip	1
#Gemcitabine**	1000 mg/m²	IV drip	1, 8
Dexamethasone**	40 mg	orally	1–4

GemOX for patients over 14 years of age [120]

Drug	Standard dose	Route of administration	Days of administration
#Gemcitabine**	1000 mg/m²	IV drip	1
#Oxaliplatin**	100 mg/m²	IV drip	1

IEP [121]

Drug	Standard dose	Route of administration	Days of administration
Ifosfamide**	2000 mg/m²	IV as a 24-hour continuous infusion (with mesna**)	1–5
#Etoposide**	125 mg/m²	IV over 2 hours	1–5
Prednisolone**	100 mg/m²	IV or orally	1–5

BeGEV for patients over 18 years of age [122]

Drug	Standard dose	Route of administration	Days of administration
#Gemcitabine**	800 mg/m²	IV infusion	1, 4
#Vinorelbine**	20 mg/m²	IV	1
#Bendamustine**	90 mg/m²	IV infusion	2, 3
#Prednisolone	100 mg/day	IV or orally	1–4
G-CSF		SC	From day 8 to day 12 or until leukocyte counts recover
Treatment is resumed on days 22–29

Brentuximab vedotin** monotherapy [54, 160, 165]

Drug	Standard dose	Route of administration	Days of administration
Brentuximab vedotin** for patients over 18 years of age	1.8 mg/kg	IV over 30 minutes	1
#Brentuximab vedotin** under 18 years of age	1.8 mg/kg	IV over 30 minutes	1
Administrations are repeated every 3 weeks. If the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation. In patients not eligible for high-dose chemotherapy with autologous hematopoietic stem cell transplantation, upon achieving stabilization or positive disease dynamics, treatment is continued up to 16, but not less than 8 cycles, in the absence of progression and with response assessment every 4 administrations. The total duration of treatment is approximately 1 year.

Drug

Standard dose

Route of administration

Days of administration

Brentuximab vedotin** for patients over 18 years of age

1.8 mg/kg

IV over 30 minutes

#Brentuximab vedotin** under 18 years of age

1.8 mg/kg

IV over 30 minutes

Administrations are repeated every 3 weeks.

If the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

In patients not eligible for high-dose chemotherapy with autologous hematopoietic stem cell transplantation, upon achieving stabilization or positive disease dynamics, treatment is continued up to 16, but not less than 8 cycles, in the absence of progression and with response assessment every 4 administrations. The total duration of treatment is approximately 1 year.

Brentuximab vedotin + #bendamustine for patients over 18 years of age [123]

Drug

Standard dose

Route of administration

Days of administration

Brentuximab vedotin**

1.8 mg/kg

IV over 30 minutes

#Bendamustine**

90 mg/m²

IV infusion

1, 2

Administrations are repeated every 3 weeks.

If the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

#Brentuximab vedotin** + #bendamustine** for patients under 18 years of age [160, 165]

Drug	Standard dose	Route of administration	Days of administration
#Brentuximab vedotin**	1.8 mg/kg	IV over 30 minutes	1
#Bendamustine**	120 mg/m²	IV infusion	1, 2
Administrations are repeated every 3 weeks.

BV-DHAP for patients over 18 years of age [124]

Drug	Standard dose	Route of administration	Days of administration
Brentuximab vedotin**	1.8 mg/kg	IV over 30 minutes	1
Dexamethasone**	40 mg	IV	1–4
#Cisplatin**	100 mg/m²	IV drip, 24-hour infusion	1
#Cytarabine**	2 g/m²	IV drip twice daily	2
Administrations are repeated every 3 weeks. For all drugs, if the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

BV-ICE for patients over 18 years of age [125]

Drug	Standard dose	Route of administration	Days of administration
#Brentuximab vedotin**	1.2 mg/kg	IV over 30 minutes	1, 8
#Etoposide**	100 mg/m²	IV drip	1–3
Ifosfamide**	5000 mg/m²	IV 24-hour infusion	2
#Carboplatin**	AUC 5	IV infusion	2
Administrations are repeated every 3 weeks. For all drugs, if the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

BV-ESHAP (BRESHAP) for patients over 18 years of age [126]

Drug	Standard dose	Route of administration	Days of administration
Brentuximab vedotin**	1.8 mg/kg	IV over 30 minutes, 1 hour before the start of chemotherapy	1
#Etoposide**	40 mg/m²	IV 2-hour infusion	1–4
Methylprednisolone**	250 mg	IV 15-minute infusion	1–4
#Cisplatin**	25 mg/m²	IV 24-hour infusion	1–4
#Cytarabine**	2 g/m²	IV 2-hour infusion	5
Administrations are repeated every 3 weeks. For all drugs, if the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

Nivo-DHAP for patients over 18 years of age [149]

Drug	Standard dose	Route of administration	Days of administration
Nivolumab**	240 mg	IV over 60 minutes	2 monotherapy administrations with an interval 14 days
Nivolumab**	480 mg	IV over 60 minutes	1
Dexamethasone**	40 mg	IV	1–4
#Cisplatin**	100 mg/m²	IV drip, 24-hour infusion	1
#Cytarabine**	2 g/m²	IV drip twice daily	2
Treatment begins with nivolumab monotherapy (2 administrations with a 14-day interval), followed by 4 cycles of combined immunochemotherapy. Nivo-DHAP combination cycles are administered every 28 days. The total duration of treatment is 20 weeks. For #cisplatin and #cytarabine**, if the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

Nivo-BeGEV for patients over 18 years of age [150]

Drug	Standard dose	Route of administration	Days of administration
Nivolumab**	3 mg/kg	IV over 60 minutes	1
#Gemcitabine**	800 mg/m²	IV infusion	1, 4
#Vinorelbine**	20 mg/m²	IV	1
#Bendamustine**	90 mg/m²	IV infusion	2, 3
Dexamethasone**	20 mg/m²	IV	1–5
Treatment is resumed on days 22–29

NICE for patients over 18 years of age [151]

Drug	Standard dose	Route of administration	Days of administration
Nivolumab**	240 mg	IV over 60 minutes	1
#Etoposide**	100 mg/m²	IV drip	1–3
Ifosfamide**	5000 mg/m²	IV 24-hour infusion	2
#Carboplatin**	AUC 5	IV infusion	2
Administrations are repeated every 3 weeks. For #etoposide, ifosfamide, and #carboplatin**, if the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

Nivolumab** monotherapy in patients over 18 years of age [55, 127]

Drug	Standard dose	Route of administration	Days of administration
Nivolumab**	3 mg/kg or 240 mg regardless of body weight, or 480 mg regardless of body weight	IV over 60 minutes	1
Treatment is resumed on day 15 (for a dose of 3 mg/kg or 240 mg) or on day 29 (for a dose of 480 mg)

Brentuximab vedotin** + nivolumab** for patients over 18 years of age [128, 129]

Drug

Standard dose

Days of administration

Brentuximab vedotin**

1.8 mg/kg

IV over 30 minutes

Nivolumab**

3 mg/kg

IV over 60 minutes (no earlier than 30 minutes after brentuximab vedotin**)

8 (cycle 1)

1 (cycles 2–4)

Treatment is resumed on day 22

For all drugs, if the patient's body weight exceeds 100 kg, a weight value of 100 kg should be used for dose calculation.

Pembrolizumab** monotherapy (1) for patients over 18 years of age [56]

Drug	Standard dose	Route of administration	Days of administration
Pembrolizumab**	200 mg	IV over 30 minutes	1
Treatment is resumed on day 22

Pembrolizumab monotherapy (2)** for patients over 18 years of age [56]

Drug	Standard dose	Route of administration	Days of administration
Pembrolizumab**	400 mg	IV over 30 minutes	1
Treatment is resumed on day 43

Pembrolizumab** monotherapy (3) for patients over 3 years of age [166,171]

Drug	Standard dose	Route of administration	Days of administration
Pembrolizumab**	2 mg/kg	IV over 30 minutes	1
Treatment is resumed on day 22

3.1.5 Therapy regimens for patients with nodular lymphocyte-predominant Hodgkin lymphoma

R-CHOP [72,168, 179, 183, 184, 191]

Drug	Standard dose	Route of administration	Days of administration
#Rituximab**	375 mg/m²	IV infusion	0 or 1
Doxorubicin**	50 mg/m²	IV infusion	1
Cyclophosphamide**	750 mg/m² (over 18 years of age) 800 mg/m² (under 18 years of age)	IV infusion	1
Vincristine**	1.4 mg/m² (maximum 2 mg)	IV, over 5–10 min	1
Prednisolone**	100 mg (over 18 years of age) 40 mg/m² (under 18 years of age)	orally IV drip	1–5 1-7
Treatment is resumed on day 22

RB for patients over 18 years of age [76, 178, 186]

Drug	Standard dose	Route of administration	Days of administration
#Rituximab**	375 mg/m²	IV infusion	0 or 1
#Bendamustine**	90 mg/m²	IV infusion	1, 2
Treatment is resumed on day 22

3.1.6 Conditioning regimens for auto-HSCT

BEAM [130,131]
Drug	Standard dose	Route of administration	Days of administration
#Carmustine**	300 mg/m²	IV infusion	–6
#Cytarabine**	200 mg/m² every 12 hours	IV infusion	–5 – –2
#Etoposide**	200 mg/m²	IV infusion	–5 – –2
#Melphalan**	140 mg/m²	IV infusion	–1
LEAM (patients over 18 years of age) [131, 132]
Drug	Standard dose	Route of administration	Days of administration
#Lomustine**	200 mg/m²	IV infusion	–6
#Cytarabine**	200 mg/m² every 12 hours	IV infusion	–5 – –2
#Etoposide**	200 mg/m²	IV infusion	–5 – –2
#Melphalan**	140 mg/m²	IV infusion	–1
Benda-EAM (patients over 18 years of age) [133,134]
Drug	Standard dose	Route of administration	Days of administration
#Bendamustine**	160–200 mg/m²	IV infusion	–7 – –6
#Cytarabine**	200 mg/m² every 12 hours	IV infusion	–5 – –2
#Etoposide**	200 mg/m²	IV infusion	–5 – –2
#Melphalan**	140 mg/m²	IV infusion	–1
BeEAC (patients over 18 years of age) [135]
Drug	Standard dose	Route of administration	Days of administration
#Bendamustine**	160–200 mg/m²	IV infusion	–6 – –5
#Cytarabine**	200 mg/m² every 12 hours	IV infusion	–4 – –1
#Etoposide**	200 mg/m²	IV infusion	–4 – –1
Cyclophosphamide**	140 mg/m²(if the patient's total body weight (TBW) is >120% of the ideal body weight (IBW), the adjusted body weight ABW25 is used for dose calculation: ABW25 = IBW + 0.25 × (TBW – IBW)) [136]	IV infusion	–4 – –1
CBV (patients over 18 years of age) [137]
Drug	Standard dose	Route of administration	Days of administration
Carmustine**	300 mg/m²	IV infusion	–6
#Etoposide**	125 mg/m² every 12 hours	IV infusion	–6 – –4
Cyclophosphamide**	1500 mg/m²	IV infusion	–6 – –3

Appendix A3.2. Recommendations for dose reduction or schedule extension during myelosuppressive cytostatic therapy

Failure to adhere to the treatment regimen (increasing inter-cycle intervals, reducing chemotherapy doses) leads to decreased treatment efficacy, progression-free survival, and overall survival of patients. Primary prophylaxis of neutropenia to ensure strict adherence to the treatment schedule in intensive first- and second-line CT regimens is achieved by administering G-CSF (short-acting and pegylated). Secondary prophylaxis of neutropenia with G-CSF is used for the same purpose when treating according to intermediate FN risk regimens.

CT treatment should be administered at full doses according to the protocol if neutrophil counts are >1×10⁹/L and platelet counts are >100×10⁹/L on the day of antineoplastic drug administration, but only provided that the nadir has already passed.

When administering intensive chemotherapy regimens that require primary FN prophylaxis using short-acting G-CSF, if the required neutrophil count is not reached by the scheduled day of antineoplastic drug administration (day 15 from the start of the previous cycle for BEACOPP-14, EACOPP-14, and BV-AVD regimens, and day 21 for the escalated BEACOPP regimen), the administration of short-acting G-CSF is continued at previous doses until neutrophils reach >1×10⁹/L with daily complete blood count monitoring, after which blood tests are repeated every other day. Treatment is resumed once the aforementioned parameters are achieved.

In the event of an interval extension when using pegylated G-CSF formulations, additional administration of short-acting G-CSF should only be considered if there is a significant interval extension of more than 7 days [37].

If blood counts recover within the subsequent 14 days, the next cycle is administered at full doses.

If blood counts do not recover for an additional 14 days, or in the event of repeated cycle delays due to myelotoxicity lasting more than 10 days, drug doses are reduced to 75% of the starting dose (except for the doses of vincristine**, bleomycin**, and prednisolone**).

If the required platelet count is not reached by the scheduled day of antineoplastic administration, subsequent blood tests are repeated on days 3, 7, 10, and 14; treatment is resumed once the above parameters are attained. If blood counts recover within an additional 14 days, the cycle is administered at full doses. If blood counts do not recover within an additional 14 days, dose reduction is performed in the next cycle according to the same scheme as for prolonged neutropenia.

The same tactics for primary FN prophylaxis (using G-CSF), dose reduction, and interval extension are applied when administering second-line treatment regimens with a high (>20%) risk of febrile neutropenia: ESHAP, BV-ESHAP, DHAP, BV-DHAP, ICE, BV-ICE, IGEV, BV-IGEV, IEP, GemOX, BeGEV.

Indications for prescribing G-CSF for secondary FN prophylaxis during treatment with intermediate FN risk regimens (<20%) are:

• an episode of febrile neutropenia with interval extension or an infection against the background of neutropenia in the interval following the previous CT cycle;

• probability of developing a life-threatening infection during the next chemotherapy cycle;

• neutropenia preventing the initiation of chemotherapy with an interval extension of more than 14 days in the previous cycle;

• inability to modify the treatment protocol (reduction of antineoplastic drug doses below the threshold level or extension of the interval between chemotherapy courses);

Factors increasing the risk of FN (≥1):

• Age over 65 years

• Severe comorbid conditions

• Hemoglobin less than 12 g/dL

• Malnutrition

• History of FN

• Absence of antimicrobial prophylaxis

• Poor performance status

• Open wounds or wound infection

• Female sex

• Cytopenia due to bone marrow tumor involvement

Appendix A3.3. Autologous hematopoietic stem cell transplantation in HL

High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation is currently the most effective treatment method for chemoresponsive cHL relapses and primary refractory cases (when refractoriness is overcome using second-line chemotherapy regimens). Unfortunately, the high efficacy of this method is associated with its high toxicity. Accordingly, the defining factor is the precise determination of indications and contraindications for transplantation.

Indications for HDCT and auto-HSCT in cHL are:

primary refractory disease course (partial remission not achieved after completion of first-line chemotherapy, progression documented);
first early relapse (remission duration less than 1 year after completion of induction treatment);
first late relapse with high tumor burden;
second late relapse;
achieving complete remission after second-line medical antineoplastic therapy administered in the above scenarios.

Contraindications for HDCT and auto-HSCT in cHL:

Absolute contraindications:

lack of remission on second-line medical antineoplastic therapy regimens;
infectious diseases in the acute phase;
diseases of the musculoskeletal system, circulatory system, digestive and respiratory organs, urogenital, endocrine, and nervous systems, as well as diseases of other organs and systems in the acute phase accompanied by persistent functional impairment;
presence of "second" malignant neoplasms not in remission;
therapy with immunosuppressive drugs (L04: immunosuppressants) or other medicinal products that may affect the self-renewal capacity and pluripotency of hematopoietic stem cells;
mental and behavioral disorders in the acute phase and/or posing a danger to the patient and others;
mental and behavioral disorders due to psychoactive substance use;
cachexia;
pregnancy;
early postoperative period with potential risks of postoperative wound infection during myelotoxic agranulocytosis.
lack of signed informed consent for transplantation.

Relative contraindications for performance:

infectious diseases in remission (foci of infection requiring sanitation);
compensated diseases of the musculoskeletal system, circulatory system, digestive and respiratory organs, urogenital, endocrine and nervous systems, as well as diseases of other organs and systems;
age over 55 years (in individual cases, increasing the age threshold is possible)
presence of human immunodeficiency virus markers in the blood;
irradiation of the lumbar spine, pelvic bones, and sternum, and/or the use of cycles including alkylating agents such as #melphalan** and lomustine** at previous stages of treatment

Patient preparation for transplantation and its execution are complex, multi-stage processes performed in medical institutions licensed for this type of medical activity. Such institutions may develop standard operating procedures (SOPs) governing the performance of HDCT and auto-HSCT. In the absence of SOPs, transplantation may be performed according to the principles, rules, and algorithms outlined below.

Mobilization of peripheral blood hematopoietic stem cells

Mobilization is a sharp increase in the number of hematopoietic stem cells (HSCs) in the peripheral blood under the influence of leukopoiesis stimulants (L03AA colony-stimulating factors).

The decision to perform mobilization and HSC collection in lymphoma patients should be made after consulting the patient at a transplant center and evaluating indications/contraindications for HDCT and auto-HSCT.

During mobilization, HSCs are identified by the immunological marker of hematopoietic progenitor cells—the CD34 antigen. This molecule is present on both the most primitive stem cells and differentiated progenitors, whereas mature hematopoietic cells lack CD34 expression. It is believed that the total pool of CD34+ cells determines the timing of hematopoietic recovery after transplantation [138,139]. There is consensus regarding the number of CD34+ cells required for rapid and successful hematopoietic recovery after transplantation [139–142]. Thus, it is currently accepted that the minimum cell count required to perform a single autologous transplantation is 2×10⁶CD34+ cells/kg of the patient's body weight, and the optimal count is 3–5×10⁶CD34+ cells/kg.

Unfortunately, in some lymphoma patients, HSC mobilization may be ineffective. Risk factors for anticipated mobilization failure (factors assessed prior to mobilization) are diverse, but none of them has 100% predictive value. Such risk factors for likely HSC mobilization failure include: a history of failed HSC mobilization, more than 3 prior chemotherapy lines before transplantation, prior radiation therapy stages before transplantation, prior use of alkylating agents (L01A Alkylating agents) (#melphalan**, lomustine**), age over 55 years, leukopenia and thrombocytopenia in the complete blood count on the eve of the planned mobilization, etc. [143].

In practice, an attempt at HSC mobilization is undertaken in the absolute majority of lymphoma patients for whom indications for HDCT and auto-HSCT have been determined, even in patients with risk factors for anticipated mobilization failure.

After the initiation of mobilization (on days 4–6), such a risk factor for mobilization failure as the circulating CD34+ cell count in the blood is evaluated. If this indicator does not reach 20 cells per 1 µL, the probability of obtaining the target HSC value for auto-HSCT is very low. In most such cases, mobilization is terminated and HSC apheresis is not performed.

HSC mobilization regimens [180, 181, 182, 188, 189, 190]

Currently, the following regimens are used for HSC mobilization in oncohematology:

G-CSF monotherapy
G-CSF following myelosuppressive chemotherapy (CT + G-CSF)
G-CSF combined with plerixafor
G-CSF (filgrastim**) as monotherapy

This regimen is also referred to as "mobilization under steady-state hematopoiesis," since the patient does not develop myelotoxic agranulocytosis (MTA).

G-CSF monotherapy mobilization regimen

G-CSF (filgrastim**) is prescribed at a dose of 10 mcg/kg/day, administered subcutaneously in the morning (or 5 mcg twice daily). Leukapheresis starts on the fourth or fifth day of G-CSF administration, provided the target number of CD34+ cells in peripheral blood is reached. Leukapheresis is initiated when their count exceeds 10–20 cells/µL. If CD34+ cells in peripheral blood are fewer than 10 cells/µL, leukapheresis must be postponed and cell counting repeated the next day. The number of leukapheresis sessions depends on the HSC collection results. Harvesting the optimal number of CD34+ cells requires 2–4 procedures (ranging from 1 to 5). On the final day of leukapheresis, G-CSF is not administered (Table A3.3.1).

Table A3.3.1. "G-CSF Monotherapy" HSC mobilization regimen

Days	1	2	3	4	5	6
G-CSF, filgrastim** 10 mcg/kg	Kh	Kh	Kh	Kh	Kh	discontinuation
Leukapheresis				V	V	V

Days

G-CSF, filgrastim**

10 mcg/kg

discontinuation

Leukapheresis

G-CSF following myelosuppressive chemotherapy

The principle of this HSC mobilization regimen is that myelosuppressive CT stimulates the proliferation of stem and progenitor cells, leading to an increased release of HSCs from the bone marrow into the blood during recovery from post-CT myelopoiesis. The use of G-CSF during this period enhances the release of HSCs.

This HSC mobilization regimen in patients with Hodgkin lymphoma is used in two modifications. In the first case, mobilization begins after a second-line myelosuppressive chemotherapy regimen (ICE, DHAP, IGEV, ESHAP, etc.). In the second case, etoposide**, cyclophosphamide**, or another antineoplastic agent is used as the myelosuppressive chemotherapeutic agent at doses causing myelosuppression.

«CT + G-CSF» HSC mobilization regimen [180, 181, 182, 188, 189]

The patient is administered an antineoplastic agent (or multiple agents as part of second-line chemotherapy), and then, following the development of MTA, stimulation of leukopoiesis with G-CSF (filgrastim**) is initiated at a dose of 5 µg/kg/day.

Provided that peripheral blood leukocytes recover and an adequate number of CD34+ cells are present among them, HSC collection procedures are initiated (typically on days 6–8 of G-CSF administration).

Figure A3.3.1 shows the algorithm for determining indications for the first leukapheresis. The number of leukaphereses depends on the HSC collection result (from 1 to 5). On the final day of leukapheresis, G-CSF is not administered.

Appendix A3. Reference Materials — Hodgkin Lymphoma

Figure A3.3.1. Algorithm for determining indications for the first leukapheresis during HSC mobilization with the «CT + G-CSF» regimen. CT — chemotherapy, MTA — myelotoxic agranulocytosis

The choice of regimen modification and antineoplastic agents depends on the patient's specific clinical situation, as well as the capabilities and preferences of the transplant center where high-dose chemotherapy is planned.

If the MTA period is complicated by a severe infection and life-threatening complications persist by the time of HSC collection, leukapheresis should be avoided. If the patient's condition is stabilized, continuation of mobilization and scheduling of HSC collection can be considered.

Below are the mobilization regimens for patients over 18 years of age using #etoposide** and cyclophosphamide** (Tables A3.3.2 and A3.3.3).

Table A3.3.2. Mobilization regimen: #etoposide** 750 mg/m²+ G-CSF 5 µg/kg [144, 188, 189]

Drug	Dosage, route of administration	Day of administration
#Etoposide**	375 mg/m² IV infusion once daily^*	+1,+2
G-CSF (filgrastim**)	5 µg/kg/day subcutaneously	from day +3 or from the moment leukocyte count drops below 1×10⁹/L

Note: ^* the concentration of #etoposide** in the solution must not exceed 0.4 mg/mL (to prevent drug precipitation)

^* if leukocyte count does not decrease, the dose of G-CSF (filgrastim**) may be increased to 10 µg/kg/day.

Table A3.3.3. Mobilization regimen: cyclophosphamide** 4 g/m²+ G-CSF (filgrastim**) 5 µg/kg [180, 181, 182]

Drug	Dosage, route of administration	Day of administration
Cyclophosphamide**	4 g/m² IV infusion 5 times daily (0.8 g/m² each)	+1
Mesna**	2.4 mg/m² IV via infusion pump over 24 hours	+1
G-CSF (filgrastim**)	5 µg/kg/day subcutaneously^*	from the moment the leukocyte count drops below 1 × 10⁹/L.

Note: ^* if leukocyte count does not decrease, the dose of G-CSF (filgrastim**) may be increased to 10 µg/kg/day.

G-CSF combined with plerixafor

The use of plerixafor improves HSC mobilization outcomes. The drug can be administered during both initial and repeat mobilization. When performing repeat mobilization after failed HSC mobilization with regimens including myelosuppressive drugs combined with G-CSF or colony-stimulating factor monotherapy, plerixafor significantly increases the likelihood of obtaining the target number of HSCs.

«G-CSF + plerixafor» HSC mobilization regimen [180, 181, 182, 188, 189, 190]

G-CSF (filgrastim**) is prescribed at a dose of 10 µg/kg/day, administered subcutaneously in the morning. On the fourth day of G-CSF administration, plerixafor is administered 12 hours before leukapheresis at a dose of 240 µg/kg subcutaneously. Based on the leukapheresis results, the need for re-administration of plerixafor is determined (Table A3.3.4). Multiple doses of plerixafor may be used.

Table A3.3.4. «G-CSF + plerixafor» HSC mobilization regimen

Days	1	2	3	4	5	6
G-CSF (filgrastim**), 10 mcg/kg	Kh	Kh	Kh	Kh	Kh
Plerixafor, 240 mcg/kg				Kh	(X)
Leukapheresis					V	V

Days

G-CSF (filgrastim**),

10 mcg/kg

Plerixafor, 240 mcg/kg

(X)

Leukapheresis

Comparative characteristics of HSC mobilization regimens

No prospective randomized trials comparing mobilization methods (growth factor alone vs. combination of G-CSF with myelosuppressive chemotherapy) in the same patient cohort have been conducted, and direct comparison of different studies is difficult. Therefore, the optimal HSC mobilization method cannot be definitively determined.

Each HSC mobilization regimen has certain advantages and disadvantages; therefore, an individualized approach is applied when choosing a treatment regimen for each specific clinical scenario (Table A3.3.5). For instance, using G-CSF as monotherapy shortens hospitalization time, avoids complications characteristic of the MTA period, and eliminates the need for transfusion therapy. This regimen is relatively safe compared to other options.

The «CT + G-CSF» regimen more frequently allows for the harvesting of a larger number of cells compared to G-CSF monotherapy, but it is associated with infectious and toxic complications during the MTA period and requires intensive supportive care, which prolongs hospitalization.

Table A3.3.5. Comparative characteristics of HSC mobilization regimens

Mobilization regimen	Advantages	Disadvantages
G-CSF monotherapy	Shorter hospital stay, clearly scheduled leukapheresis dates, no need for antibiotic therapy or replacement transfusion therapy	Reduced efficacy in heavily pretreated patients
CT + G-CSF	High mobilization efficacy	Cytopenia Infectious Complications Blood component transfusions No fixed scheduling for leukapheresis Unsafe in patients with significant comorbidities

Mobilization regimen

Advantages

Disadvantages

G-CSF monotherapy

Shorter hospital stay, clearly scheduled leukapheresis dates, no need for antibiotic therapy or replacement transfusion therapy

Reduced efficacy in heavily pretreated patients

CT + G-CSF

High mobilization efficacy

Cytopenia

Infectious Complications

Blood component transfusions

No fixed scheduling for leukapheresis

Unsafe in patients with significant comorbidities

Leukapheresis and cryopreservation of HSCs

Leukapheresis

Leukapheresis is a semi-selective extracorporeal hemocorrection method based on the separation of plasma and blood cells using centrifugal force and the isolation of the leukocyte fraction from the blood [145].

As mentioned above, the main criterion for predicting successful HSC collection during mobilization is the CD34+ cell count in peripheral blood on the day of the planned first leukapheresis. Starting HSC collection too early requires more procedures, leading to increased financial and labor costs. Moreover, an increased number of leukaphereses leads to an increase in the total volume of the harvested product. Consequently, a larger amount of cryoprotectant (dimethyl sulfoxide — DMSO) is required, which may cause adverse reactions during subsequent intravenous infusion during auto-HSCT [146].

On the day of the intended first collection, a complete blood count and flow cytometric CD34+ cell count are performed.

If the peripheral blood CD34+ cell count is greater than 10–20/µL, the first leukapheresis can be initiated.

If the absolute CD34+ cell count in the blood is greater than 20/µL, there is a high probability of harvesting the graft in 1–2 leukapheresis procedures.

When CD34+ cells are detected in the blood at a count of 10–20/µL, 2–4 leukapheresis procedures are typically required.

If the CD34+ cell count is less than 10/µL, it is advisable to refrain from cell collection on that day and repeat the analysis the following day.

If the CD34+ cell count is less than 5/µL, the option of discontinuing mobilization or potentially using plerixafor should be discussed.

A significant decrease in hemoglobin or platelets caused by prior chemotherapy may be a contraindication to starting leukapheresis. In such situations, transfusion support prior to the procedure may be administered.

A sample of HSCs is taken from the obtained product to determine the CD34+ cell content using a flow cytometer. Next, the CD34+ cells in the harvested leukocyte concentrate are counted. By determining the proportion of CD34+ cells among all leukocytes in the concentrate, the number of CD34+ cells per kilogram of the patient's body weight is calculated.

The resulting biomaterial with a cryoprotectant is transferred into a cryopreservation container, and air bubbles are thoroughly removed.

Freezing and storage of the biomaterial are carried out in a container with liquid nitrogen vapors.

Evaluation of HL patients before auto-HSCT

Before performing autologous hematopoietic stem cell transplantation, it is necessary to determine the phase of the disease (remission status), evaluate the patient's somatic status and hematopoietic function. For this purpose, all patients undergo a routine set of examinations, including both laboratory and instrumental methods.

Regimens of preparative conditioning for auto-HSCT

The goal of high-dose chemotherapy (conditioning regimen) before auto-HSCT is to eliminate tumor cells remaining after antitumor therapy with minimal toxic impact on organ systems.

In the absence of randomized trials comparing various conditioning regimens, the choice of regimen is made taking into account the experience and capabilities of the transplant center, as well as the patient's individual characteristics.

High-dose chemotherapy regimens used in patients with HL are presented in Appendix A3.1.

Infusion of autologous hematopoietic stem cells.

Hematopoietic stem cell infusion is performed into a central venous catheter observing aseptic and antiseptic principles.

The time interval from the end of chemotherapy to HSC infusion is at least 24 hours.

For the first administration, the cryopreserved HSC bag with the maximum cellularity is selected. When handling the bag, the use of metal objects (clamps, forceps, etc.) is prohibited. If there are multiple bags of cryopreserved HSCs, it is advisable to take breaks between infusions. In some cases, administration of HSCs over 2 days is permissible (elderly, debilitated patients).

Cryopreserved HSCs are thawed in a water bath or a programmable thawer at a temperature of 37^°C.

In some cases, trimeperidine** at a standard dosage is used prior to administering the leukoconcentrate into the central venous catheter.

The initial infusion rate of HSCs is 3–5 ml/min (4–5 minutes), after which the rate can be increased to the maximum possible. During and after HSC infusions, vital signs are monitored: BP, HR, RR.

If hemolysis develops, the infusion of the next bag is suspended until complications are resolved.

Two hours after the completion of the infusion, a general general-clinical blood chemistry test and a general (clinical) urinalysis are performed to rule out hemolysis.

Appendix B. Physician Action Algorithms

Regimen B1. First-line therapy for patients with cHL over 18 years of age

Regimen B2. First-line therapy for children and adolescents under 18 years of age with cHL

Regimen B3. Treatment of cHL relapses

Appendix C. Patient Information

Lymphomas are tumors originating from lymphoid cells. Lymphoma is not a single disease; it is a large group comprising more than 30 different diseases that differ from each other in their manifestations, course, and response to treatment. Lymphomas behave and are treated completely differently. Therefore, simply saying "lymphoma" means nothing—to understand how to treat it, one must know the specific variant of lymphoma.

Hodgkin lymphoma can occur at any age, but the disease is most common in young people, with the peak occurring in the 16 to 34 age group. Children and older adults, especially those over 55, can also develop Hodgkin lymphoma.

The diagnosis of Hodgkin lymphoma is established only after examining the affected tissue obtained via biopsy. The diagnosis is confirmed only if typical cells called Berezovsky-Sternberg-Reed cells are found. In recent years, the diagnosis of Hodgkin lymphoma and other lymphomas has improved due to the use of a new method—immunophenotyping—which allows precise identification of tumor cells by markers on their surface. This research method is very important for the correct choice of therapy taking into account modern capabilities. Hodgkin lymphoma is better studied than any other type of lymphoma. Fortunately, with modern treatment methods, more than 80% of patients who develop Hodgkin lymphoma are completely cured of this disease.

There are no specific symptoms unique only to this disease. Similar complaints and signs can occur in many other diseases. Often the disease begins as if it were a cold or respiratory infection that drags on for some reason. The disease may begin with painless enlargement of lymph nodes.

The most common signs of Hodgkin lymphoma:

• painless enlargement of lymph nodes;

• fever not explained by infection or other causes;

• sweating, especially at night (wet pillow in the mornings);

• unexplained weight loss;

• unusual fatigue and weakness

The most frequent symptom of Hodgkin lymphoma is enlargement of lymph nodes, most commonly in the neck, less frequently in other body areas. The temperature is usually around 37.5°C in the evenings. Profuse night sweats are very characteristic, although this symptom is difficult to evaluate: it is hot in summer, and heating is intense in winter. Numerous other complaints and signs may be observed depending on the location of the tumor focus. Pain is typically absent. When the disease is localized in the mediastinum, closer to the sternum, discomfort behind the sternum is possible. A small number of patients experience agonizing skin itching leading to excoriations. About 5% of patients note pain in enlarged lymph nodes after alcohol consumption. This is a rare symptom, but it is characteristic of Hodgkin lymphoma. Its cause is unknown.

More than 80% of all patients with Hodgkin lymphoma can be cured, with examinations and treatment carried out mainly on an outpatient basis. Most patients receive combination therapy, including chemotherapy combined with radiation therapy. Under certain circumstances, high-dose therapy and transplantation of autologous bone marrow or stem cells are used. Radiation therapy as the sole treatment method is practically never used nowadays.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649–65 [147]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Status (scores)	Description of the patient's general condition
0	Fully active, able to carry on all pre-disease performance without restriction.
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework or office work).
2	The patient is treated on an outpatient basis, is capable of self-care, but cannot work. Spends more than 50% of waking time upright.
3	The patient is capable of only limited self-care, spending more than 50% of waking time in a chair or bed.
4	Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5	Dead

Appendix G2. PET/CT treatment response evaluation scale (Deauville scale)

Original title: The Deauville five point scale

Source: Meignan M. et al. Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009;50(8):1257–1260 [106,148]

Type: rating scale

Purpose: evaluation of treatment efficacy based on PET/CT scan results.

Content and interpretation: for standardization, reproducibility, and comparability of PET/CT results obtained in different medical institutions, visual analysis of PET data using a 5-point scale is used to assess treatment response in lymphoma patients. The intensity of 18F-FDG uptake in the pathological lesion is compared with the intensity of radiopharmaceutical uptake in unchanged regions of the mediastinum or in the right lobe of the liver:

1 point — characterized by the absence of tracer uptake in the previously identified pathological lesion;

2 points — tracer uptake in the pathological lesion does not exceed the intensity of tracer uptake in unchanged regions of the mediastinum;

3 points — tracer uptake in the pathological lesion is higher than in the mediastinum, but does not exceed the tracer uptake in the right lobe of the liver;

4 points — tracer uptake in the pathological lesion is moderately higher than in the liver;

5 points — tracer uptake in the pathological lesion is markedly (more than 3 times) higher than in the liver, or new disease-related pathological lesions appear.

The concept of X-scores has also been introduced to characterize the presence of 18F-FDG uptake foci of unclear, likely inflammatory origin, the connection of which with the underlying disease is unlikely.

Interpretation of PET/CT results according to the Deauville scale:

Negative PET/CT results — 1, 2, and 3 points indicate a complete metabolic response to treatment, regardless of the presence and volume of residual mass.
Positive PET/CT results — 4 and 5 points. Positive PET/CT results indicate various conditions:
4 or 5 points with a decrease in tracer uptake intensity in the pathological lesion compared to baseline data — partial metabolic response;
4 or 5 points without a change in tracer uptake intensity in the pathological lesion compared to baseline data — stable disease;
4 or 5 points with an increase in tracer uptake intensity in the pathological lesion compared to baseline data, with or without the appearance of new disease-related lesions — progressive disease.
Interpretation of PET/CT results on the Deauville scale is carried out taking into account clinical and baseline PET data, the treatment stage, and other treatment response indicators.
The presence of a single pathological lesion of tracer uptake that influences the decision on the feasibility of completing treatment requires a biopsy of this lesion.

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